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CN101083993A - Heterocyclic derivatives and their use as therapeutic agents - Google Patents

Heterocyclic derivatives and their use as therapeutic agents Download PDF

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Publication number
CN101083993A
CN101083993A CNA2005800397871A CN200580039787A CN101083993A CN 101083993 A CN101083993 A CN 101083993A CN A2005800397871 A CNA2005800397871 A CN A2005800397871A CN 200580039787 A CN200580039787 A CN 200580039787A CN 101083993 A CN101083993 A CN 101083993A
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alkyl
heteroaryl
cyclic hydrocarbon
hydrogen
hydrocarbon radical
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Inventor
拉金德·坎博日
张载辉
傅健民
万德纳·拉伊纳
塞尔戈·斯维里多夫
维什努墨西·库德穆鲁
纳加斯瑞·柴卡
刘世峰
孙绍毅
侯端杰
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Xenon Pharmaceuticals Inc
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Xenon Pharmaceuticals Inc
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
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    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
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    • C07—ORGANIC CHEMISTRY
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    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D237/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

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Abstract

Methods of treating an SCD-mediated disease or condition in a mammal, preferebly a human, are disclosed, wherein the methods comprise administering to a mammal in need thereof a compound of formula (I): where x, y, G, J, K, L, M, W, R<2>, R<3>, R<5> , R<5a>, R<6>, R<6a>, R<7>, R<7a>, R<8> and R<8a> are difined herein. Pharmaceutical compositions comprising the compounds of formula (I) are also disclosed.

Description

Hete rocyclic derivatives and as the purposes of stearoyl coa desaturase inhibitors
Invention field
The present invention relates generally to the stearoyl coa desaturase inhibitors field, and the purposes of this compounds in treating and/or preventing multiple human diseases, described stearoyl coa desaturase inhibitors for example is a Hete rocyclic derivatives, described human diseases comprises the disease by stearoyl-coa-desaturase (SCD) mediation, preferably by the disease of SCD1 mediation, diseases such as especially relevant disease, cardiovascular disease, diabetes, obesity, metabolism syndrome with the lipid level that raises.
Background of invention
The catalysis of acyl group desaturase is from the formation of two keys in the fatty acid of de novo synthesis in diet source or the liver.Mammal is synthesized at least three kinds of specific fatty acid desaturases of different chain length, but the introducing of this fatty acid desaturase catalysis two keys on δ-9, δ-6 and δ-5 position.Stearoyl-coa-desaturase (SCDs) is introduced two keys on the C9-C10 position of satisfied fatty acid.Preferred substrate is palmityl CoA (16: 0) and stearyl CoA (18: 0), and it can change into palmitoleoyl CoA (16: 1) and oleoyl CoA (18: 1) respectively.The gained monounsaturated fatty acid is the substrate that is used to incorporate into phospholipid, triglyceride and cholesteryl ester.
Many mammiferous SCD genes have been cloned.For example, from rat, cloned two kinds of genes (SCD1, SCD2), and isolated four kinds of SCD genes (SCD1,2,3 and 4) from mice.Though from the 1970's with regard to known basic biological chemistry action (Jeffcoat, people such as R., Elsevier Science (1984), Vol.4, the pp.85-112 of SCD in rat and mice; De Antueno, RJ, Lipids (1993), Vol.28, No.4 pp.285-290), but only just finds with human disease processes direct correlation is arranged recently.
In the mankind, characterized out single S CD gene, i.e. SCD1.Described SCD1 among people's such as Brownlie the PCT publication application WO 01/62954, this paper is incorporated herein by reference its disclosed full content.Identified second kind of people SCD isozyme recently, and because itself and other mice or rat isozyme have sequence homology seldom, therefore its name is people SCD5 or hSCD5 (PCT publication application WO 02/26944, this paper is incorporated by reference in its entirety).
Up to now, specificity suppress or regulate SCD active for the chemical compound of micromolecular similar medicine be unknown.Some long chain hydrocarbon has been used to study the SCD activity in the past.Known example comprises thia fatty acid, cyclopropene fatty acid and some conjugated linoleic acid isomers.Especially, think suitable-12, the trans-10 conjugated linoleic acid suppresses the SCD enzymatic activity and reduces the abundance of SCD1 mRNA, and suitable-9, and anti--11 conjugated linoleic acids then can not.Also known cyclopropene fatty acid suppresses the SCD activity such as the cyclopropene fatty acid of finding in sterculia nobilis's seed and cotton seed.For example, sterculic acid (8-(2-octyl group cyclopropanyl) is sad) and malvalic acid (7-(2-octyl group cyclopropanyl) enanthic acid) are respectively the sterculia nobilis's acyl group fatty acid that has the cyclopropylene ring on its C9-C10 position and the C8 and the C16 derivant of Radix Malvae sylvestris acyl group fatty acid.Think that these reagent can suppress the SCD enzymatic activity by the direct interaction with enzyme, thereby suppress δ-9 desaturation.Can suppress active other reagent of SCD and comprise thia fatty acid, have the fatty acid of sulfxoy part as 9-sulfo-stearic acid (it is sad to be also referred to as 8-nonyl sulfo-) and other.
These known δ-9 desaturase active regulators can not be used for the treatment of disease and the disease relevant with the SCD1 biological activity.Known SCD inhibitor compound does not all have selectivity to SCD or δ-9 desaturase, because it also suppresses other desaturase and enzyme.Thia fatty acid, conjugated linoleic acid and cyclopropylene fatty acid (malvalic acid and sterculic acid) can not reasonably use under the physiological dose, neither the bioactive specific inhibitor of SCD1, they but demonstrate the intersection inhibitory action to other desaturase on the contrary, and especially the cyclopropylene fatty acid is to the intersection inhibitory action of δ-5 and δ-6 desaturase.
The micromolecular inhibitor that lacks the SCD enzymatic activity is main science and medical science setback, because prominent evidence shows that the SCD activity directly relates to general human disease processes at present: for example referring to Attie, A.D. wait people " Relationship between stearoyl-CoAdesaturate activity and plasma triglycerides in human and mousehypertriglyceridemia (relation in the mankind and the mice hypertriglyceridemia between stearoyl-coa-desaturase activity and plasma triglyceride) ", J.Lipid Res. (2002), Vol.43, No.11, pp.1899-907; Cohen, P. wait people " Role for stearoyl-CoA desaturate-1 inleptin-mediated weight loss (effect of stearoyl-coa-desaturase-1 in the losing weight of leptin mediation) ", Science (2002), Vol.297, No.5579, pp.240-3; Ntambi; J.M. wait people " Loss of stearoyl-CoA desaturate-1 function protectsmice against adiposity (the forfeiture protection mice of stearoyl-coa-desaturase-1 function avoids obesity) "; Proc.Natl.Acad.Sci.U SA. (2002); Vol.99; No.7, pp.11482-6.
The present invention can be used for regulating the SCD activity and regulates lipid level by providing, especially a class noval chemical compound of blood plasma lipide level has solved the problems referred to above, described chemical compound can be used for treating the disease of SCD mediation, as disease relevant with dyslipidemia and lipid metabolic disorder, especially treatment is diseases such as the disease relevant with the lipid level that raises, cardiovascular disease, diabetes, obesity, metabolism syndrome.
Summary of the invention
The invention provides and regulate the active Hete rocyclic derivatives of stearoyl-coa-desaturase.The pharmaceutical composition that uses this analog derivative adjusting active method of stearoyl-coa-desaturase and comprise this analog derivative has also been contained in the present invention.
Therefore, on the one hand, the invention provides general formula (I) chemical compound, its stereoisomer, its enantiomer or its tautomer, the acceptable salt of its medicine, its pharmaceutical composition or its prodrug:
Figure A20058003978700131
Wherein:
X and y all are 0,1,2 or 3 independently;
G is-N (R 4)-,-O-,-S (O) t-(wherein t is 0,1 or 2) ,-C (R 4)=or-C (R 4)=C (R 4)-;
J and K all are N or C (R independently 10);
L and M all be independently-N=,-N (R 4)-or-C (R 4)=, prerequisite is to be-C (R as G 4)=or-C (R 4)=C (R 4)-time, L and M are not-C (R simultaneously 4)=;
W be chemical bond ,-N (R 1) C (O)-,-C (O) N (R 1)-,-OC (O) N (R 1)-,-N (R 1) C (O) N (R 1)-,-O-,-N (R 1)-,-S (O) t-(wherein t is 0,1 or 2) ,-N (R 1) S (O) p-(wherein p is 1 or 2) ,-S (O) pN (R 1)-(wherein p be 1 or 2) ,-C (O)-,-OS (O) 2N (R 1)-,-OC (O)-,-C (O) O-or-N (R 1) C (O) O-;
Each R 1Be independently selected from hydrogen, C 1-C 12Alkyl, C 2-C 12Hydroxyalkyl, C 4-C 12Cyclic hydrocarbon radical alkyl and C 7-C 19Aralkyl;
R 2Be selected from C 1-C 12Alkyl, C 2-C 12Thiazolinyl, C 2-C 12Hydroxyalkyl, C 2-C 12Hydroxy alkenyl, C 2-C 12Alkoxyalkyl, C 3-C 12Cyclic hydrocarbon radical, C 4-C 12Cyclic hydrocarbon radical alkyl, aryl, C 7-C 19Aralkyl, C 3-C 12Heterocyclic radical, C 3-C 12Heterocyclic radical alkyl, C 1-C 12Heteroaryl and C 3-C 12Heteroaryl alkyl;
Or R 2For having the multiring structure of 2 to 4 rings, wherein said ring is independently selected from cyclic hydrocarbon radical, heterocyclic radical, aryl and heteroaryl, and wherein part or all of ring can condense each other;
R 3Be selected from hydrogen, C 1-C 12Alkyl, C 2-C 12Thiazolinyl, C 2-C 12Hydroxyalkyl, C 2-C 12Hydroxy alkenyl, C 2-C 12Alkoxyalkyl, C 3-C 12Cyclic hydrocarbon radical, C 4-C 12Cyclic hydrocarbon radical alkyl, aryl, C 7-C 19Aralkyl, C 3-C 12Heterocyclic radical, C 3-C 12Heterocyclic radical alkyl, C 1-C 12Heteroaryl and C 3-C 12Heteroaryl alkyl;
Or R 3Can be the multiring structure with 2 to 4 rings, wherein said ring is independently selected from cyclic hydrocarbon radical, heterocyclic radical, aryl and heteroaryl, and wherein part or all of ring can condense each other;
Each R 4Be independently selected from hydrogen, fluorine, chlorine, C 1-C 12Alkyl, C 1-C 12Alkoxyl, haloalkyl, cyano group, nitro or-N (R 9) 2
Perhaps two adjacent R 4Group can form aryl, heteroaryl or heterocyclic ring system with the carbon that it connected;
R 5, R 5a, R 6, R 6a, R 7, R 7a, R 8And R 8aAll be independently selected from hydrogen or C 1-C 3Alkyl;
Perhaps R 5With R 5aR together, 6With R 6aTogether or R 7With R 7aTogether or R 8With R 8aBe oxo group together;
Perhaps R 5, R 5a, R 6And R 6aOne of and R 7, R 7a, R 8And R 8aOne of form chemical bond or alkylidene bridge together, and all the other R 5, R 5a, R 6, R 6a, R 7, R 7a, R 8And R 8aAll be independently selected from hydrogen or C 1-C 3Alkyl;
Each R 9Be independently selected from hydrogen or C 1-C 6Alkyl; And
R 10Be independently selected from hydrogen, fluorine, chlorine, C 1-C 12Alkyl or C 1-C 12Alkoxyl.
Should be appreciated that the scope of the invention relevant with above-mentioned general formula (I) chemical compound be not intended to be encompassed in previous open in open especially and/or claimed chemical compound, include but not limited to following open in disclosed especially chemical compound:
The disclosed patent application WO 03/076400 of PCT;
The disclosed patent application WO 03/066604 of PCT;
The disclosed patent application WO 01/019822 of PCT;
The disclosed patent application WO 99/021834 of PCT;
The disclosed patent application WO 99/020606 of PCT;
The disclosed patent application WO 98/001446 of PCT;
The disclosed patent application WO 94/012495 of PCT;
No. 0 300 526, the disclosed patent application in Europe;
No. 0 156 433, the disclosed patent application in Europe;
No. 0 055 583, the disclosed patent application in Europe;
No. 0 009 655, the disclosed patent application in Europe;
United States Patent (USP) the 5th, 719, No. 154; And
United States Patent (USP) the 5th, 494, No. 908.
On the other hand, it is mammiferous to the invention provides treatment, preferably be people's the disease of SCD mediation or the method for morbid state, and wherein this method comprises and will treat the mammal administration of the invention described above chemical compound of effective dose to this treatment of needs.
On the other hand, the invention provides be used for the treatment of, disease that prevention and/or diagnosis are relevant with the SCD biological activity or the chemical compound or the pharmaceutical composition of morbid state, described disease or morbid state for example are the disease that comprises cardiovascular disorder and/or metabolism syndrome (comprising dyslipidemia, insulin resistant and obesity).
On the other hand, the present invention provides prevention or the treatment disease relevant with the lipid level of rising or the method for morbid state for the patient of lipid level with rising, this lipid level for example is the blood plasma lipide level, especially triglyceride or the cholesterol levels for raising, described method comprise that compositions disclosed herein with treatment or prevention effective dose is to described patient's administration.The invention still further relates to noval chemical compound with the treatment ability that reduces animal lipid level, especially triglyceride and cholesterol levels.
On the other hand, the invention provides the pharmaceutical composition that comprises aforesaid The compounds of this invention and pharmaceutically-acceptable excipients.In one embodiment, the present invention relates in the medicine acceptable carrier, contain the pharmaceutical composition of a certain amount of The compounds of this invention, this amount is for working as animal, preferably to mammal, during most preferably to the human patients administration, effectively regulate triglyceride levels or treatment disease relevant and lipid metabolic disorder with dyslipidemia.In the embodiment of this compositions, described patient is before described compound administration and before described chemical compound exists with the amount of the described lipid level of effective reduction, and this patient has had the lipid level of rising, as plasma triglyceride or the cholesterol that raises.
On the other hand, the invention provides that treatment suffers from the disease of stearoyl-coa-desaturase (SCD) mediation or the patient or the prevention patient of morbid state develops into the disease of stearoyl-coa-desaturase (SCD) mediation or the method for morbid state, this method comprises that chemical compound with the treatment effective dose is to the patient that suffers from this disease or morbid state or be in patient's administration of suffering among this disease or the morbid state danger, this chemical compound suppresses the SCD activity to described patient's administration the time.
On the other hand, the invention provides use is related to a series of diseases of lipid metabolism by the compounds for treating of method discriminating disclosed herein method.Therefore, herein disclosed is the described active a series of chemical compounds that have based on the screening analysis, this screening is analyzed and is used for identifying from the test compounds storehouse biological activity of regulating described SCD and can be used for treating the human diseases relevant with the serum levels of lipid or the therapeutic agent of morbid state, and described lipid is triglyceride, VLDL, HDL, LDL and/or T-CHOL for example.
Detailed description of the invention
Definition
Indicate some chemical group of name herein in front by the contracted notation that shows the total number of carbon atoms of in specifying chemical group, finding.For example, C 7-C 12Alkyl is described has the alkyl as giving a definition that adds up to 7 to 12 carbon atoms, and C 4-C 12The cyclic hydrocarbon radical alkyl is described has the cyclic hydrocarbon radical alkyl as giving a definition that adds up to 4 to 12 carbon atoms.The total number of carbon atoms in the contracted notation does not comprise the carbon in the substituent group that may be present in described group.
Therefore, unless opposite explanation is arranged in addition, used following term has following connotation in description and the claims:
" methoxyl group " refers to-OCH 3Base.
" cyano group " refers to-the CN base.
" nitro " refers to-NO 2Base.
" trifluoromethyl " refers to-CF 3Base.
" oxo " refers to=the O substituent group.
" sulfo-" refers to=the S substituent group.
" alkyl " refers to the hydrocarbon chain group of straight or branched, described hydrocarbon chain group is only formed, is not contained unsaturated by carbon and hydrogen atom, has 1 to 12 carbon atom, preferred 1 to 8 carbon atom or 1 to 6 carbon atom, and be connected with the remainder of molecule by singly-bound, for example methyl, ethyl, n-pro-pyl, 1-Methylethyl (isopropyl), normal-butyl, n-pentyl, 1,1-dimethyl ethyl (tert-butyl group) or the like.Unless offer some clarification in addition in the description, alkyl can be replaced arbitrarily by one of following group: alkyl, thiazolinyl, halogen, haloalkenyl group, cyano group, nitro, aryl, cyclic hydrocarbon radical, heterocyclic radical, heteroaryl ,-OR 14,-OC (O)-R 14,-N (R 14) 2,-C (O) R 14,-C (O) OR 14,-C (O) N (R 14) 2,-N (R 14) C (O) OR 16,-N (R 14) C (O) R 16,-N (R 14) (S (O) tR 16) (wherein t is 1 to 2) ,-S (O) tOR 16(wherein t is 1 to 2) ,-S (O) tR 16(wherein t is 0 to 2) and-S (O) tN (R 14) 2(wherein t is 1 to 2), wherein each R 14Be hydrogen, alkyl, haloalkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl (being replaced arbitrarily), aralkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl or heteroaryl alkyl independently by one or more group that is selected from halogen or haloalkyl; And each R 16Be alkyl, haloalkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl or heteroaryl alkyl, and wherein except as otherwise noted, each above-mentioned substituent group is unsubstituted.
" C 1-C 3Alkyl " refer to contain the alkyl of the above-mentioned definition of 1 to 3 carbon atom.C 1-C 3Alkyl can be optionally substituted as defined to alkyl group.
" C 1-C 6Alkyl " refer to contain the alkyl of the above-mentioned definition of 1 to 6 carbon atom.C 1-C 6Alkyl can be optionally substituted as defined to alkyl group.
" C 1-C 12Alkyl " refer to contain the alkyl of the above-mentioned definition of 1 to 12 carbon atom.C 1-C 12Alkyl can be optionally substituted as defined to alkyl group.
" C 2-C 6Alkyl " refer to contain the alkyl of the above-mentioned definition of 2 to 6 carbon atoms.C 2-C 6Alkyl can be optionally substituted as defined to alkyl group.
" C 3-C 6Alkyl " refer to contain the alkyl of the above-mentioned definition of 3 to 6 carbon atoms.C 3-C 6Alkyl can be optionally substituted as defined to alkyl group.
" C 3-C 12Alkyl " refer to contain the alkyl of the above-mentioned definition of 3 to 12 carbon atoms.C 3-C 12Alkyl can be optionally substituted as defined to alkyl group.
" C 6-C 12Alkyl " refer to contain the alkyl of the above-mentioned definition of 6 to 12 carbon atoms.C 6-C 12Alkyl can be optionally substituted as defined to alkyl group.
" C 7-C 12Alkyl " refer to contain the alkyl of the above-mentioned definition of 7 to 12 carbon atoms.C 7-C 12Alkyl can be optionally substituted as defined to alkyl group.
" thiazolinyl " only refer to by carbon form, contain at least one two key with hydrogen atom, have 2 to 12 carbon atoms, the hydrocarbon chain group of preferred 2 to 8 carbon atoms and the straight or branched that is connected with the remainder of molecule by singly-bound, for example vinyl, third-1-thiazolinyl, but-1-ene base, penta-1-thiazolinyl, penta-1,4-dialkylene or the like.Unless offer some clarification in addition in the description, thiazolinyl can be replaced arbitrarily by one of following group: alkyl, thiazolinyl, halogen, haloalkyl, haloalkenyl group, cyano group, nitro, aryl, aralkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroaryl alkyl ,-OR 14,-OC (O)-R 14,-N (R 14) 2,-C (O) R 14,-C (O) OR 14,-C (O) N (R 14) 2,-N (R 14) C (O) OR 16,-N (R 14) C (O) R 16,-N (R 14) (S (O) tR 16) (wherein t is 1 to 2) ,-S (O) tOR 16(wherein t is 1 to 2) ,-S (O) tR 16(wherein t is 0 to 2) and-S (O) tN (R 14) 2(wherein t is 1 to 2), wherein each R 14Be hydrogen, alkyl, haloalkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl or heteroaryl alkyl independently; And each R 16Be alkyl, haloalkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl or heteroaryl alkyl, and wherein each above-mentioned substituent group is unsubstituted.
" C 3-C 12Thiazolinyl " refer to contain the thiazolinyl of the above-mentioned definition of 3 to 12 carbon atoms.C 3-C 12Thiazolinyl can be optionally substituted as defined to alkenyl group.
" C 2-C 12Thiazolinyl " refer to contain the thiazolinyl of the above-mentioned definition of 2 to 12 carbon atoms.C 2-C 12Thiazolinyl can be as being optionally substituted to the above-mentioned definition of alkenyl group.
" alkylidene " reach " alkylidene chain " only refer to by carbon form, do not contain unsaturated with hydrogen and have 1 to 12 carbon atom, preferred 1 to 8 carbon atom, the bivalent hydrocarbon chain of straight or branched that the remainder of molecule is connected with group, for example methylene, ethylidene, propylidene, positive butylidene or the like.Alkylidene chain can be connected with group with the remainder of molecule by carbon in this chain or any two carbon that pass through in this chain.Alkylidene chain can be replaced arbitrarily by one of following group: alkyl, thiazolinyl, halogen, haloalkenyl group, cyano group, nitro, aryl, cyclic hydrocarbon radical, heterocyclic radical, heteroaryl ,-OR 14,-OC (O)-R 14,-N (R 14) 2,-C (O) R 14,-C (O) OR 14,-C (O) N (R 14) 2,-N (R 14) C (O) OR 16,-N (R 14) C (O) R 16,-N (R 14) (S (O) tR 16) (wherein t is 1 to 2) ,-S (O) tOR 16(wherein t is 1 to 2) ,-S (O) tR 16(wherein t is 0 to 2) and-S (O) tN (R 14) 2(wherein t is 1 to 2), wherein each R 14Be hydrogen, alkyl, haloalkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl (being replaced arbitrarily), aralkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl or heteroaryl alkyl independently by one or more group that is selected from halogen or haloalkyl; And each R 16Be alkyl, haloalkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl or heteroaryl alkyl, and wherein except as otherwise noted, each above-mentioned substituent group is unsubstituted.
" alkenylene " reaches " alkenylene chain " and only refers to the straight or branched bivalent hydrocarbon chain being formed, contain at least one two key and had 2 to 12 carbon atoms, the remainder of molecule is connected with group by carbon and hydrogen, for example ethenylidene, allylidene, butenylidene or the like just.The alkenylene chain can be connected with the remainder of molecule and can be connected with described group by two keys or singly-bound by singly-bound.The junction point of the remainder of alkylidene chain and molecule with and with the junction point of group residue can be by a carbon or wantonly two carbon in the chain.The alkenylene chain can be replaced arbitrarily by one of following group: alkyl, thiazolinyl, halogen, haloalkenyl group, cyano group, nitro, aryl, cyclic hydrocarbon radical, heterocyclic radical, heteroaryl ,-OR 14,-OC (O)-R 14,-N (R 14) 2,-C (O) R 14,-C (O) OR 14,-C (O) N (R 14) 2,-N (R 14) C (O) OR 16,-N (R 14) C (O) R 16,-N (R 14) (S (O) tR 16) (wherein t is 1 to 2) ,-S (O) tOR 16(wherein t is 1 to 2) ,-S (O) tR 16(wherein t is 0 to 2) and-S (O) tN (R 14) 2(wherein t is 1 to 2), wherein each R 14Be hydrogen, alkyl, haloalkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl (being replaced arbitrarily), aralkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl or heteroaryl alkyl independently by one or more group that is selected from halogen or haloalkyl; And each R 16Be alkyl, haloalkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl or heteroaryl alkyl, and wherein except as otherwise noted, each above-mentioned substituent group is unsubstituted.
" alkylidene bridge " only refer to by carbon form, do not contain unsaturated with hydrogen and have 1 to 12 carbon atom, preferably have 1 to 8 carbon atom, be connected the bivalence hydrocarbon bridge of straight or branched of two different carbon of identical ring structure, for example methylene, ethylidene, propylidene, positive butylidene or the like.Alkylidene bridge can connect any two carbon in the described ring structure.
" alkoxyl " refers to general formula-OR aGroup, R wherein aAlkyl for above-mentioned definition.The moieties of alkoxy base can be as being optionally substituted to the above-mentioned definition of alkyl group.
" C 1-C 6Alkoxyl " refer to contain the alkoxyl of the above-mentioned definition of 1 to 6 carbon atom.C 1-C 6The moieties of alkoxy base can be as being optionally substituted to the above-mentioned definition of alkyl group.
" C 1-C 12Alkoxyl " refer to contain the alkoxyl of the above-mentioned definition of 1 to 12 carbon atom.
C 1-C 12The moieties of alkoxy base can be as being optionally substituted to the above-mentioned definition of alkyl group.
" C 3-C 12Alkoxyl " refer to contain the alkoxyl of the above-mentioned definition of 3 to 12 carbon atoms.C 3-C 12The moieties of alkoxyl can be as being optionally substituted to the above-mentioned definition of alkyl group.
" alkoxyalkyl " refers to general formula-R a-O-R aGroup, each R wherein aBe the alkyl of above-mentioned definition independently.Oxygen atom can with any carbon Cheng Jian in arbitrary alkyl group.Each moieties of alkoxy-alkyl group can be as being optionally substituted to the above-mentioned definition of alkyl group.
" C 2-C 12Alkoxyalkyl " refer to contain the alkoxy-alkyl group of the above-mentioned definition of 2 to 12 carbon atoms.C 2-C 12Each moieties of alkoxy-alkyl group can be as being optionally substituted to the above-mentioned definition of alkyl group.
" C 3Alkoxyalkyl " refer to contain the alkoxy-alkyl group of the above-mentioned definition of 3 carbon atoms.C 3Each moieties of alkoxy-alkyl group can be optionally substituted as defined to the abovementioned alkyl group.
" C 3-C 12Alkoxyalkyl " refer to contain the alkoxy-alkyl group of the above-mentioned definition of 3 to 12 carbon atoms.C 3-C 12Each moieties of alkoxy-alkyl group can be as being optionally substituted to the above-mentioned definition of alkyl group.
" alkyl sulphonyl " refers to general formula-S (O) 2R aGroup, wherein R aAlkyl for above-mentioned definition.The moieties of alkyl sulphonyl group can be as being optionally substituted to the above-mentioned definition of alkyl group.
" C 1-C 6Alkyl sulphonyl " refer to have the alkyl sulphonyl group of the above-mentioned definition of 1 to 6 carbon atom.C 1-C 6The alkyl sulphonyl group can be as being optionally substituted to the above-mentioned definition of alkyl sulphonyl group.
" aryl " refers to only be formed and contained by hydrogen and carbon the aromatic series monocycle or the polycyclic hydrocarbon member ring systems of 6 to 19 carbon atoms, preferred 6 to 10 carbon atoms, and wherein said member ring systems can be a fractional saturation or saturated fully.Aryl includes but not limited to the group such as fluorenyl, phenyl and naphthyl.Unless offer some clarification in addition in the description, term " aryl " or prefix " virtue-(ar-) " (as " aralkyl ") refer to comprise the aromatic yl group that is replaced arbitrarily by one or more substituent groups, described substituent group be selected from alkyl, thiazolinyl, halogen, haloalkyl, haloalkenyl group, cyano group, nitro, aryl, aralkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroaryl alkyl ,-R 15-OR 14,-R 15-OC (O)-R 14,-R 15-N (R 14) 2,-R 15-C (O) R 14,-R 15-C (O) OR 14,-R 15-C (O) N (R 14) 2,-R 15-N (R 14) C (O) OR 16,-R 15-N (R 14) C (O) R 16,-R 15-N (R 14) (S (O) tR 16) (wherein t is 1 to 2) ,-R 15-S (O) tOR 16(wherein t is 1 to 2) ,-R 15-S (O) tR 16(wherein t is 0 to 2) and-R 15-S (O) tN (R 14) 2(wherein t is 1 to 2), wherein each R 14Be hydrogen, alkyl, haloalkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl or heteroaryl alkyl independently; Each R 15Be the alkylidene chain or the alkenylene chain of chemical bond or straight or branched independently; And each R 16Be alkyl, haloalkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl or heteroaryl alkyl, and wherein each above-mentioned substituent group is unsubstituted.
" aralkyl " refers to general formula-R aR bGroup, R wherein aAlkyl and R for above-mentioned definition bBe one or more aromatic yl groups of above-mentioned definition, for example benzyl, diphenyl methyl or the like.The aryl moiety of aromatic alkyl group can be as being optionally substituted to the above-mentioned definition of aromatic yl group.The moieties of aromatic alkyl group can be as being optionally substituted to the above-mentioned definition of alkyl group.
" C 7-C 12 aralkyl " refer to contain the aromatic alkyl group of the above-mentioned definition of 7 to 12 carbon atoms.C 7-C 12The aryl moiety of aromatic alkyl group can be as being optionally substituted to the above-mentioned definition of aromatic yl group.C 7-C 1The moieties of 2 aromatic alkyl groups can be as being optionally substituted to the above-mentioned definition of alkyl group.
" C 7-C 19Aralkyl " refer to contain the aromatic alkyl group of the above-mentioned definition of 7 to 19 carbon atoms.C 7-C 19The aryl moiety of aromatic alkyl group can be as being optionally substituted to the above-mentioned definition of aromatic yl group.C 7-C 19The moieties of aromatic alkyl group can be as being optionally substituted to the above-mentioned definition of alkyl group.
" C 13-C 19Aralkyl " refer to contain the aromatic alkyl group of the above-mentioned definition of 13 to 19 carbon atoms.C 13-C 19The aryl moiety of aromatic alkyl group can be as being optionally substituted to the above-mentioned definition of aromatic yl group.C 13-C 19The moieties of aromatic alkyl group can be as being optionally substituted to the above-mentioned definition of alkyl group.
" arylalkenyl " refers to general formula-R cR bGroup, R wherein cThiazolinyl and R for above-mentioned definition bBe one or more aryl of above-mentioned definition, it can be optionally substituted as mentioned above.The aryl moiety of arylalkenyl group can be as being optionally substituted to the above-mentioned definition of aromatic yl group.The alkenyl part of arylalkenyl group can be as being optionally substituted to the above-mentioned definition of alkenyl group.
" aryloxy group " refers to general formula-OR bGroup, R wherein bAryl for above-mentioned definition.The aryl moiety of aryloxy group can be optionally substituted as above-mentioned definition.
" aryl-C 1-C 6Alkyl " refer to general formula-R h-R iGroup, R wherein hFor having the unbranched alkyl group of 1 to 6 carbon, and R iBe the aromatic yl group that is connected with the terminal carbon of this alkyl group.
" cyclic hydrocarbon radical " only refers to be formed, to have 3 to 15 carbon atoms with hydrogen atom, preferably to be had 3 to 12 carbon atoms and be stable non-aromatic monocycle or dicyclic hydrocarbon group saturated or unsaturated, that be connected with the remainder of molecule by singly-bound, for example cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, ring decyl (decalinyl) or the like by carbon.Unless offer some clarification in the description, otherwise term " cyclic hydrocarbon radical " refers to comprise the cyclic hydrocarbon radical that is replaced arbitrarily by one or more substituent groups, this substituent group be selected from alkyl, thiazolinyl, halogen, haloalkyl, haloalkenyl group, cyano group, nitro, aryl, aralkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroaryl alkyl ,-R 15-OR 14,-R 15-OC (O)-R 14,-R 15-N (R 14) 2,-R 15-C (O) R 14,-R 15-C (O) OR 14,-R 15-C (O) N (R 14) 2,-R 15-N (R 14) C (O) OR 16,-R 15-N (R 14) C (O) R 16,-R 15-N (R 14) (S (O) tR 16) (wherein t is 1 to 2) ,-R 15-S (O) tOR 16(wherein t is 1 to 2) ,-R 15-S (O) tR 16(wherein t is 0 to 2) and-R 15-S (O) tN (R 14) 2(wherein t is 1 to 2), wherein each R 14Be hydrogen, alkyl, haloalkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl or heteroaryl alkyl independently; Each R 15Be the alkylidene chain or the alkenylene chain of chemical bond or straight or branched independently; And each R 16Be alkyl, haloalkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl or heteroaryl alkyl, and wherein each above-mentioned substituent group is unsubstituted.
" C 3-C 6Cyclic hydrocarbon radical " refer to have the cyclic hydrocarbon radical of the above-mentioned definition of 3 to 6 carbon atoms.C 3-C 6The cyclic hydrocarbon radical group can be as being optionally substituted to the above-mentioned definition of cyclic hydrocarbon radical group.
" C 3-C 12Cyclic hydrocarbon radical " refer to have the cyclic hydrocarbon radical of the above-mentioned definition of 3 to 12 carbon atoms.C 3-C 12The cyclic hydrocarbon radical group can be as being optionally substituted to the above-mentioned definition of cyclic hydrocarbon radical group.
" cyclic hydrocarbon radical alkyl " refers to general formula-R aR dGroup, wherein R aBe the alkyl group of above-mentioned definition, and R dCyclic hydrocarbon radical group for above-mentioned definition.The cyclic hydrocarbon radical part of cyclic hydrocarbon radical alkyl group can be as being optionally substituted to the above-mentioned definition of cyclic hydrocarbon radical group.The moieties of cyclic hydrocarbon radical alkyl group can be as being optionally substituted to the above-mentioned definition of alkyl group.
" C 4-C 12The cyclic hydrocarbon radical alkyl " refer to have the cyclic hydrocarbon radical alkyl group of the above-mentioned definition of 4 to 12 carbon atoms.C 4-C 12The cyclic hydrocarbon radical alkyl group can be as being optionally substituted to the above-mentioned definition of cyclic hydrocarbon radical alkyl group.
" halogen " refers to bromine, chlorine, fluorine or iodine.
" haloalkyl " refers to by the alkyl group of the above-mentioned definition of the halogen group of one or more above-mentioned definition replacement, for example trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1-methyl fluoride-2-fluoro ethyl, 3-bromo-2-fluoropropyl, 1-bromomethyl-2-bromoethyl or the like.The moieties of halogenated alkyl group can be as being optionally substituted to the above-mentioned definition of alkyl group.
" haloalkenyl group " refers to by the alkenyl group of the above-mentioned definition of the halogen group of one or more above-mentioned definition replacement, for example 2-bromo vinyl, 3-bromine third-1-thiazolinyl or the like.The alkenyl part of haloalkenyl group group can be as being optionally substituted to the above-mentioned definition of alkenyl group.
" heterocyclic radical " refers to be selected from 3 to 18 yuan of stable non-aromatic cyclic groups that the hetero atom of nitrogen, oxygen and sulfur is formed by carbon atom and 1 to 5.For the purposes of the present invention, described heterocyclic radical can be monocycle, dicyclo, three ring or Fourth Ring member ring systems, and it can comprise fused rings system or bridged-ring system, and the nitrogen in the described heterocyclic radical, carbon or sulphur atom can be randomly oxidized; Nitrogen-atoms can be randomly by quaternized; And the heterocyclic radical group can fractional saturation or all saturated.The example of this class heterocyclic radical includes but not limited to dioxy cyclopenta, Decahydroisoquinolinpreparation base, imidazolinyl, imidazolidinyl, isothiazole alkyl, isoxazole alkyl, morpholinyl, octahydro indyl, octahydro isoindolyl, 2-oxo piperazinyl, 2-oxo-piperidine base, 2-oxo-pyrrolidine base, oxazolidinyl, piperidyl, piperazinyl, 4-piperidone base, pyrrolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrofuran base, trithiane base, THP trtrahydropyranyl, thio-morpholinyl, thiomorpholine base, 1-oxo-thio-morpholinyl and 1,1-dioxo-thio-morpholinyl.Unless offer some clarification in addition in the description, otherwise term " heterocyclic radical " refers to comprise the heterocyclic radical of the above-mentioned definition that is replaced arbitrarily by one or more substituent group, this substituent group be selected from alkyl, thiazolinyl, halogen, haloalkyl, haloalkenyl group, cyano group, oxo, sulfo-, nitro, aryl, aralkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroaryl alkyl ,-R 15-OR 14,-R 15-OC (O)-R 14,-R 15-N (R 14) 2,-R 15-C (O) R 14,-R 15-C (O) OR 14,-R 15-C (O) N (R 14) 2,-R 15-N (R 14) C (O) OR 16,-R 15-N (R 14) C (O) R 16,-R 15-N (R 14) (S (O) tR 16) (wherein t is 1 to 2) ,-R 15-S (O) tOR 16(wherein t is 1 to 2) ,-R 15-S (O) tR 16(wherein t is 0 to 2) and-R 15-S (O) tN (R 14) 2(wherein t is 1 to 2), wherein each R 14Be hydrogen, alkyl, thiazolinyl, haloalkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl or heteroaryl alkyl independently; Each R 15Be the alkylidene chain or the alkenylene chain of chemical bond or straight or branched independently; And each R 16Be alkyl, thiazolinyl, haloalkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl or heteroaryl alkyl, and wherein each above-mentioned substituent group is unsubstituted.
" C 3-C 12Heterocyclic radical " refer to have the heterocyclic radical of the above-mentioned definition of 3 to 12 carbon.C 3-C 12Heterocyclic radical can be as being optionally substituted to the above-mentioned definition of heterocyclic radical group.
" heterocyclic radical alkyl " refers to general formula-R aR eGroup, wherein R aAlkyl group and R for above-mentioned definition eBe the heterocyclic radical group of above-mentioned definition, and if heterocyclic radical be nitrogenous heterocyclic radical, then this heterocyclic radical can be connected with alkyl group at this nitrogen-atoms place.The moieties of heterocyclic radical alkyl group can be as being optionally substituted to the above-mentioned definition of alkyl group.The heterocyclic radical part of heterocyclic radical alkyl group can be as being optionally substituted to the above-mentioned definition of heterocyclic radical group.
" C 3-C 12The heterocyclic radical alkyl " refer to have the heterocyclic radical alkyl of the above-mentioned definition of 3 to 12 carbon.C 3-C 12The heterocyclic radical alkyl group can be as being optionally substituted to the above-mentioned definition of heterocyclic radical alkyl group.
" heteroaryl " refers to be selected from 5 to 18 yuan of aromatic ring groups that the hetero atom of nitrogen, oxygen and sulfur is formed by carbon atom and 1 to 5.For the purposes of the present invention, described heteroaryl can be monocycle, dicyclo, three ring or Fourth Ring member ring systems, and it can comprise fused rings system or bridged-ring system; And the nitrogen in the heteroaryl, carbon or sulphur atom can be randomly oxidized; Nitrogen-atoms can be randomly by quaternized.Example includes but not limited to azepine  base; acridinyl; benzimidazolyl; benzothiazolyl; the benzindole base; the diazosulfide base; benzo naphtho-furan base benzoxazolyl; benzo dioxolyl (benzodioxolyl) Ben Bing Evil English base (benzodioxinyl); benzopyranyl; the .alpha.-5:6-benzopyran ketone group; benzofuranyl; the benzofuran ketone group; benzothienyl (benzo thiophenyl); the benzotriazole base; benzo [4; 6] imidazo [1; 2-a] pyridine radicals; carbazyl; the cinnolines base; dibenzofuran group; furyl; furanonyl; isothiazolyl; imidazole radicals; indyl; indazolyl; isoindolyl; indolinyl; iso-dihydro-indole-group; indolizine base isoxazolyl; naphthyridinyl oxadiazole base; 2-oxo azepine  base oxazolyl; Oxyranyle; phenazinyl; phenothiazinyl phenoxazine group; the 2 base; pteridine radicals; purine radicals; pyrrole radicals; pyrazolyl; pyridine radicals; pyrazinyl; pyrimidine radicals; pyridazinyl; quinazolyl; quinoxalinyl; quinolyl; quininuclidinyl; isoquinolyl; thiazolyl; thiadiazolyl group; triazolyl; tetrazole radical; triazine radical and thiophenyl.Unless offer some clarification in addition in the description, otherwise term " heteroaryl " is intended to comprise the heteroaryl groups of the above-mentioned definition that is replaced arbitrarily by one or more substituent group, this substituent group be selected from alkyl, thiazolinyl, halogen, haloalkyl, haloalkenyl group, cyano group, oxo, sulfo-, nitro, aryl, aralkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroaryl alkyl ,-R 15-OR 14,-R 15-OC (O)-R 14,-R 15-N (R 14) 2,-R 15-C (O) R 14,-R 15-C (O) OR 14,-R 15-C (O) N (R 14) 2,-R 15-N (R 14) C (O) OR 16,-R 15-N (R 14) C (O) R 16,-R 15-N (R 14) (S (O) tR 16) (wherein t is 1 to 2) ,-R 15-S (O) tOR 16(wherein t is 1 to 2) ,-R 15-S (O) tR 16(wherein t is 0 to 2) and-R 15-S (O) tN (R 14) 2(wherein t is 1 to 2), wherein each R 14Be hydrogen, alkyl, thiazolinyl, haloalkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl or heteroaryl alkyl independently; Each R 15Be the alkylidene chain or the alkenylene chain of chemical bond or straight or branched independently; And each R 16Be alkyl, thiazolinyl, haloalkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl or heteroaryl alkyl, and wherein each above-mentioned substituent group is unsubstituted.
" C 1-C 12Heteroaryl " refer to have the heteroaryl of the above-mentioned definition of 1 to 12 carbon atom.C 1-C 12Heteroaryl groups can be as being optionally substituted to the above-mentioned definition of heteroaryl groups.
" C 5-C 12Heteroaryl " refer to have the heteroaryl of the above-mentioned definition of 5 to 12 carbon atoms.C 5-C 12Heteroaryl can be as being optionally substituted to the above-mentioned definition of heteroaryl groups.
" heteroaryl alkyl " refers to general formula-R aR fGroup, wherein R aBe the alkyl of above-mentioned definition, and R fHeteroaryl for above-mentioned definition.The heteroaryl moieties of heteroaryl alkyl group can be as being optionally substituted to the above-mentioned definition of heteroaryl groups.The moieties of heteroaryl alkyl group can be as being optionally substituted to the above-mentioned definition of alkyl group.
" C 3-C 12Heteroaryl alkyl " refer to have the heteroaryl alkyl of the above-mentioned definition of 3 to 12 carbon atoms.C 3-C 12The heteroaryl alkyl group can be as being optionally substituted to the above-mentioned definition of heteroaryl alkyl group.
" heteroaryl ring alkyl " refers to general formula-R dR fGroup, wherein R dBe the cyclic hydrocarbon radical group of above-mentioned definition, and R fHeteroaryl groups for above-mentioned definition.The cyclic hydrocarbon radical part of heteroaryl ring hydrocarbyl group can be as being optionally substituted to the above-mentioned definition of cyclic hydrocarbon radical group.The heteroaryl moieties of heteroaryl ring hydrocarbyl group can be as being optionally substituted to the above-mentioned definition of heteroaryl groups.
" heteroaryl thiazolinyl " refers to general formula-R bR fBase carbon, wherein R bBe the alkenyl group of above-mentioned definition, and R fHeteroaryl groups for above-mentioned definition.The heteroaryl moieties of heteroaryl alkenyl group can be as being optionally substituted to the above-mentioned definition of heteroaryl groups.The alkenyl part of heteroaryl alkenyl group can be as being optionally substituted to the above-mentioned definition of alkenyl group.
" hydroxyalkyl " refers to general formula-R a-OH group, wherein R aAlkyl for above-mentioned definition.Hydroxyl can be connected with this alkyl on the either carbon in this alkyl group.The moieties of hydroxyalkyl group can be as being optionally substituted to the above-mentioned definition of alkyl group.
" C 2-C 12Hydroxyalkyl " refer to contain the hydroxyalkyl group of the above-mentioned definition of 2 to 12 carbon atoms.C 2-C 12The moieties of hydroxyalkyl group can be as being optionally substituted to the above-mentioned definition of alkyl group.
" C 3-C 12Hydroxyalkyl " refer to contain the hydroxyalkyl group of the above-mentioned definition of 3 to 12 carbon atoms.C 3-C 12The moieties of hydroxyalkyl group can be as being optionally substituted to the above-mentioned definition of alkyl group.
" C 7-C 12Hydroxyalkyl " refer to contain the hydroxyalkyl group of the above-mentioned definition of 7 to 12 carbon atoms.C 7-C 12The moieties of hydroxyalkyl group can be as being optionally substituted to the above-mentioned definition of alkyl group.
" hydroxy alkenyl " refers to general formula-R c-OH group, wherein R cThiazolinyl for above-mentioned definition.Hydroxyl can be connected with this thiazolinyl on the either carbon in this alkenyl group.The alkenyl part of hydroxy alkenyl group can be as being optionally substituted to the above-mentioned definition of alkenyl group.
" C 2-C 12Hydroxy alkenyl " refer to contain the hydroxy alkenyl of the above-mentioned definition of 2 to 12 carbon atoms.C 2-C 12The alkenyl part of hydroxy alkenyl group can be as being optionally substituted to the above-mentioned definition of alkenyl group.
" C 3-C 12Hydroxy alkenyl " refer to contain the hydroxy alkenyl of the above-mentioned definition of 3 to 12 carbon atoms.C 3-C 12The alkenyl part of hydroxy alkenyl group can be as being optionally substituted to the above-mentioned definition of alkenyl group.
" hydroxyl-C 1-C 6-alkyl " refer to general formula-R h-OH group, wherein R hFor having the straight chained alkyl of 1 to 6 carbon atom, and hydroxyl is connected with terminal carbon.
" tri haloalkyl " refers to by the alkyl group of the above-mentioned definition of the halogen group of three above-mentioned definition replacement, for example trifluoromethyl.The moieties of tri haloalkyl group can be as being optionally substituted to the above-mentioned definition of alkyl group.
" C 1-C 6Tri haloalkyl " refer to have the tri haloalkyl of the above-mentioned definition of 1 to 6 carbon atom.C 1-C 6Tri haloalkyl can be as being optionally substituted to the above-mentioned definition of tri haloalkyl group.
" three halogenated alkoxies " refers to general formula-OR gGroup, wherein R gTri haloalkyl for above-mentioned definition.The tri haloalkyl part of three halo alkoxy groups can be as being optionally substituted to the above-mentioned definition of tri haloalkyl group.
" C 1-C 6Three halogenated alkoxies " refer to have three halo alkoxy groups of the above-mentioned definition of 1 to 6 carbon atom.C 1-C 6Three halo alkoxy groups can be as being optionally substituted to the above-mentioned definition of three halo alkoxy groups.
" multiring structure " refers to comprise the multi-ring member ring systems of 2 to 4 rings, and wherein said ring is independently selected from cyclic hydrocarbon radical, aryl, heterocyclic radical or the heteroaryl of above-mentioned definition.Each cyclic hydrocarbon radical can be as being optionally substituted to the above-mentioned definition of cyclic hydrocarbon radical group.Each aryl can be as being optionally substituted to the above-mentioned definition of aromatic yl group.Each heterocyclic radical can be as being optionally substituted to the above-mentioned definition of heterocyclic radical group.Each heteroaryl can be as being optionally substituted to the above-mentioned definition of heteroaryl groups.Described ring can be connected with other ring by chemical bond, and perhaps some or all rings can condense each other.Example includes but not limited to the cyclic hydrocarbon radical group that replaced by aromatic yl group; By the cyclic hydrocarbon radical group that aromatic yl group replaces, this aromatic yl group is replaced by another aromatic yl group successively; Or the like.
" prodrug " refers to can be under physiological condition or be converted into the chemical compound of bioactive compound of the present invention by solvolysis.Therefore, term " prodrug " refers to the metabolic precursor thereof of the acceptable The compounds of this invention of medicine.To the individual administration of this prodrug of needs the time, prodrug can be a non-activity, but is converted into reactive compound of the present invention in vivo.Prodrug transforms usually in vivo fast, produces parent compound of the present invention, is for example transformed fast by the hydrolysis in blood.Before drug compound in mammalian organism, provide advantage about dissolubility, histocompatibility or extended release (referring to Bundgard usually, H., Design of Prodrugs (design of prodrug) (1985), pp.7-9,21-24 (Elsevier, Amsterdam)).
At Higuchi, T., Deng the people, " Pro-drugs as Novel Delivery Systems (prodrug is as the induction system of novelty); " A.C.S.Symposium Series, the Bioreversible Carriers in Drug Design that Vol.14 and Edward B.Roche edit (the biological reversible carrier in the medicine design), American Pharmaceutical Association and Pergamon Press, the discussion of relevant prodrug was provided in 1987, and this paper is incorporated herein by reference the full text of the two.
Term " prodrug " also is intended to comprise when this prodrug during to the mammalian subject administration, is discharged the carrier of any covalent bonds of reactive compound of the present invention in vivo.By modifying the prodrug that the functional group that exists in the The compounds of this invention prepares The compounds of this invention in such a way, this mode is this modification or with routine operation or be cracked into parent compound of the present invention in vivo.Prodrug comprises chemical compound of the present invention, wherein hydroxyl, amino or mercapto groups and group Cheng Jian arbitrarily, with the prodrug of The compounds of this invention during to the administration of mammal donor, the group cracking of described Cheng Jian is to form free hydroxyl, free amino or free sulfydryl respectively.The example of prodrug includes but not limited to acetate, formates and the benzoate derivant etc. of alcohol in the The compounds of this invention or amine functional group.
" stable chemical compound " and " stable structure " are intended to represent that chemical compound is enough stable so that can isolate the purity of useful degree from reactant mixture, and prescription is effective therapeutic agent.
" mammal " comprises the mankind and domestic animal, as cat, Canis familiaris L., pig, cattle, sheep, goat, horse, rabbit etc.
" arbitrarily " or " at random " refer to that the situation of narrating subsequently may occur or may not occur, and this narration comprises situation that described incident or situation occur and the situation that can not occur.For example, " aryl that replaces arbitrarily " refers to that described aryl may be substituted or may not be substituted, and this narration comprises the aromatic yl group and the unsubstituted aromatic yl group of replacement.
" medicine acceptable carrier, diluent or excipient " includes but not limited to be approved acceptable any adjuvant, carrier, excipient, fluidizer, sweeting agent, diluent, antiseptic, dyestuff/coloring agent, flavour reinforcers, surfactant, wetting agent, dispersant, suspending agent, stabilizing agent, isotonic agent, solvent or the emulsifying agent that has used by Food and Drug Administration in the mankind or domestic animal.
" the acceptable salt of medicine " comprises acid-adducting salt and alkali adduct.
" the acceptable acid-adducting salt of medicine " refers to keep the biological effectiveness of free alkali and those salt of character, described acid-adducting salt is suitable and is to use mineral acid or organic acid forms in biology or others, mineral acid is such as but not limited to hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid etc., organic acid is such as but not limited to acetic acid, 2, the 2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, the 4-acetaminobenzoic acid, dextrocamphoric acid., Camphora-10-sulfonic acid, capric acid, caproic acid, sad, carbonic acid, cinnamic acid, citric acid, the cyclohexyl sulfamic acid, lauryl sulphate acid, ethane-1, the 2-disulfonic acid, ethane sulfonic acid, the 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, glactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, 1,3-propanedicarboxylic acid, 2-oxo-1,3-propanedicarboxylic acid, phosphoglycerol, glycolic, hippuric acid, isopropylformic acid., lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, Loprazolam, mucic acid, naphthalene-1, the 5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxyl-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, Palmic acid, pamoic acid, propanoic acid, pyroglutamic acid, acetone acid, salicylic acid, the 4-aminosallcylic acid, decanedioic acid, stearic acid, succinic acid, tartaric acid, Hydrogen thiocyanate, p-methyl benzenesulfonic acid, trifluoroacetic acid, undecylenic acid etc.
" the acceptable alkali adduct of medicine " refers to keep the biological effectiveness of free acid and those salt of character, and described alkali adduct is suitable in biology or others.Adding inorganic base or organic base prepare these salt in free acid.Include but not limited to sodium, potassium, lithium, ammonium, calcium, magnesium, ferrum, zinc, copper, manganese, aluminum salt etc. by the deutero-salt of inorganic base.Preferred inorganic salt is that ammonium, sodium, potassium, calcium close magnesium salt.Include but not limited to primary amine by the deutero-salt of organic base, the salt of secondary amine and tertiary amine, the salt of amine of replacement that comprises the amine of naturally occurring replacement, the salt of cyclammonium and deacidite, for example ammonia, 2-aminopropane., trimethylamine, diethylamine, triethylamine, tripropyl amine (TPA), diethanolamine, ethanolamine, dimethylaminoethanol, the 2-dimethylaminoethanol, 2-diethylaminoethanol, hexanamine, lysine, arginine, histidine, caffeine, procaine, Hai Baming (hydrabamine), choline, betanin, benzylamine (benethamine), benzene ethylenediamine (benzathine), ethylenediamine, glucamine, methylglucosamine, theobromine, triethanolamine, tromethane, purine, piperazine, piperidines, N-ethylpiperidine, the salt of polyamino resin or the like.Particularly preferred organic base is 2-aminopropane., diethylamine, ethanolamine, trimethylamine, hexanamine, choline and caffeine.
Crystallization can produce the solvate of The compounds of this invention usually.Term used herein " solvate " refers to comprise the aggregation of the one or more The compounds of this invention molecules that have one or more solvent molecules.Described solvent can be water, and described in this case solvate is a hydrate.Perhaps, described solvent may be organic solvent.Therefore, The compounds of this invention can exist with the form of hydrate, comprises monohydrate, dihydrate, semihydrate, half as much again hydrate, trihydrate, tetrahydrate or the like, and the corresponding solvent form exists.Chemical compound of the present invention can be real solvate, but in other cases, chemical compound of the present invention can only keep indefinite water or be the mixture of water and some indefinite solvent.
" pharmaceutical composition " refers to that common being used for of accepting is delivered to described bioactive compound such as the formed preparation of the intravital medium of mammals such as people in chemical compound of the present invention and this area.This class medium comprises the acceptable supporting agent of all medicines, diluent or excipient.
" treatment effective dose " refers to when to the mammal administration, and during preferably to people's administration, it is mammiferous that chemical compound of the present invention is enough to effective treatment (the following definition), the disease of preferred people's SCD mediation or the amount of morbid state.According to described chemical compound, morbid state and seriousness thereof and mammiferous age to be treated, the amount of forming the The compounds of this invention of " treat effective amount " will difference, but those of ordinary skills can determine the amount of The compounds of this invention routinely according to himself knowledge and the disclosure.
The disease paid close attention to suffering from or the mammal of disease have been contained in " treatment " used herein or " treatment ", treat disease or the morbid state of being paid close attention among the preferred mankind, and comprise:
(i) prevent disease or morbid state take place in mammal, especially work as this mammal susceptible in described morbid state, but are not diagnosed as this morbid state as yet;
(ii) suppress described disease or morbid state, promptly stop its development; Or
(iii) alleviate described disease or morbid state, even described disease or morbid state disappear.
Term used herein " disease " reaches " morbid state " can exchange use mutually, maybe can be different, because special disease or morbid state may not have known virulence factor (therefore can not solve with etiology), therefore it is not acknowledged as disease but is inappropriate morbid state or symptom, and wherein the clinician has identified special serial symptom more or less.
Chemical compound of the present invention or the acceptable salt of its medicine can contain one or more asymmetric centers, and therefore produce enantiomer, diastereomer and other stereoisomer form, can according to the absolute stereo chemistry it is defined as (R)-or (S)-, or be amino acid whose (D)-or (L)-.The present invention is intended to comprise all possible isomers of this class, with and racemic form and optical voidness form.Can use chiral synthon or chiral reagent to prepare (+) and (-), (R) of optically-active-and (S)-or (D)-and (L)-isomer, or use such as the routine techniquess such as HPLC that adopt chiral column and split.When chemical compound as herein described contained the two keys of alkene or other how much asymmetric centers, unless expressly stated otherwise,, otherwise described chemical compound was intended to comprise E and Z geometric isomer.Same, also be intended to comprise all tautomeric forms.
" stereoisomer " refers to what the same atoms by identical key bonding constituted, but has the chemical compound of not interchangeable different three dimensional structures.The present invention includes multiple stereoisomer and composition thereof, and comprise that " enantiomer ", enantiomer refer to that molecule is two stereoisomers that can not synergetic mirror image each other.
" tautomer " refers to that proton moves to another atom with a part from an atom of molecule.The present invention includes the tautomer of any described chemical compound.
Chemical name principle used herein and structure chart use and according to the used chemical name feature of Chemdraw 7.0.1 version (can be from Cambridgesoft Corp., Cambridge, MA obtains).For the chemical name of complexity used herein, this substituent group of name before the group that substituent group is connected.For example, the cyclopropyl ethyl comprises having the substituent ethyl main chain of cyclopropyl.In the chemical structural drawing, except some carbon atom is assumed to be the enough hydrogen atoms of bonding to finish the coordination valence, all keys are all determined.
For example, general formula (I) chemical compound, wherein x and y are 1; G is-C (H)=C (H)-; J and K are N; L and M are-N=, and W is-N (H) C (O)-; R 2Be 2-cyclopropyl ethyl and R 3Be 5-methyl fluoride pyridine-2-base, i.e. following formula: compound:
Figure A20058003978700311
Called after 6-[4-(3-5-flumethiazine-2-yl) six hydrogen piperazine-1-yl in this article] pyridazine-3-carboxylic acid (2-cyclopropyl ethyl) amide.
Some group of The compounds of this invention is described to the connection between two parts of The compounds of this invention in this article.For example, in as shown in the formula (I):
Figure A20058003978700312
W for example is described to-N (R 1) C (O)-,-C (O) N (R 1)-or-N (R 1) C (O) N (R 1)-.This narration be intended to with R 2The W group that group connects is described below: R 2-N (R 1) C (O)-, R 2-C (O) N (R 1)-or R 2-N (R 1) C (O) N (R 1)-.In other words, in view of above-mentioned general formula (I), the description of W linking group meaned by the left side read the right.
The working of an invention scheme
In above-mentioned general formula (I) chemical compound in summary of the invention, an embodiment is following chemical compound, wherein J and K the two be N, promptly have the chemical compound of following formula (Ia):
Figure A20058003978700321
In this embodiment, an embodiment is general formula (Ia) chemical compound, wherein
X and y are 1;
G is-C (R 4)=C (R 4)-;
L and M are-N=;
W is-N (R 1) C (O)-,-C (O) N (R 1)-,-OC (O) N (R 1)-,-N (R 1) C (O) N (R 1)-,-N (R 1) S (O) p-(wherein p is 1 or 2) ,-S (O) pN (R 1)-(wherein p be 1 or 2) ,-OS (O) 2N (R 1)-,-C (O) O-or-N (R 1) C (O) O-;
Each R 1Be independently selected from hydrogen, C 1-C 12Alkyl, C 2-C 12Hydroxyalkyl, C 4-C 12Cyclic hydrocarbon radical alkyl and C 7-C 19Aralkyl;
R 2Be selected from C 7-C 12Alkyl, C 2-C 12Thiazolinyl, C 7-C 12Hydroxyalkyl, C 2-C 12Hydroxy alkenyl, C 2-C 12Alkoxyalkyl, C 3-C 12Cyclic hydrocarbon radical, C 4-C 12Cyclic hydrocarbon radical alkyl, aryl, C 13-C 19Aralkyl, C 3-C 12Heterocyclic radical, C 3-C 12Heterocyclic radical alkyl, C 1-C 12Heteroaryl and C 3-C 12Heteroaryl alkyl;
R 3Be selected from aryl, C 3-C 12Heterocyclic radical and C 1-C 12Heteroaryl; And
Each R 4Be independently selected from hydrogen, fluorine, chlorine, C 1-C 12Alkyl, C 1-C 12Alkoxyl, haloalkyl, cyano group, nitro or-N (R 9) 2
R 5, R 5a, R 6, R 6a, R 7, R 7a, R 8And R 8aAll independently be selected from hydrogen or C 1-C 3Alkyl;
Prerequisite is R 2Be not C 5-C 10Pyrazinyl alkyl, pyriconyl, pyrrolidone-base, methylimidazolyl or the phenyl that is replaced by amino.
In this embodiment, an embodiment is R wherein 3Be those chemical compounds of aryl.
The particular of this embodiment includes but not limited to be selected from following chemical compound:
6-[4-(4-fluorophenyl)-piperazine-1-yl]-pyridazine-3-carboxylic acid (2-cyclopropyl ethyl) amide; And
6-[4-(3-trifluoromethyl)-piperazine-1-yl]-pyridazine-3-carboxylic acid (2-cyclopropyl ethyl) amide.
In this embodiment, another embodiment is R wherein 3Be C 1-C 12The chemical compound of heteroaryl.
The particular of this embodiment includes but not limited to be selected from following chemical compound:
6-(4-benzoxazole-2-base-piperazine-1-yl) pyridazine-3-carboxylic acid (2-cyclopropyl ethyl) amide;
6-(4-benzothiazole-2-base-piperazine-1-yl) pyridazine-3-carboxylic acid (2-cyclopropyl ethyl) amide;
6-(4-quinazoline-4-base-piperazine-1-yl) pyridazine-3-carboxylic acid (2-cyclopropyl ethyl) amide;
6-[4-(3-5-flumethiazine-2-yl) piperazine-1-yl] pyridazine-3-carboxylic acid (2-cyclopropyl ethyl) amide;
6-(4-benzo [d] isothiazole-3-base-piperazine-1-yl) pyridazine-3-carboxylic acid (2-cyclopropyl ethyl) amide;
6-(4-pyridine-2-base-piperazine-1-yl) pyridazine-3-carboxylic acid (2-cyclopropyl ethyl) amide; And
6-[4-(3-oxo-3H-iso-indoles-1-yl) piperazine-1-yl) pyridazine-3-carboxylic acid (2-cyclopropyl ethyl) amide.
In another embodiment of the present invention, general formula (I) chemical compound does not comprise following " excluded " chemical compound, these chemical compounds are named with its chemical abstracts registry no (Chemical AbstractRegistry Nos.) (" RN "), and by american chemical association chemical abstracts service (Chemical Abstract Service of the American ChemicalSoceity) (Washington, D.C.) definition:
RN?331242-58-1；
RN?202135-24-8；
RN?202135-25-9；
RE?202135-26-0；
RN?202135-27-1；
RN?202135-28-2；
RN?202135-36-2；
RN?100241-46-1；
RN?100241-62-1；
RN?100224-53-1；
RN?100224-54-2；
RN?100224-67-7；
RN?100241-07-4；
RN?100241-08-5；
RN?100241-46-1；
RN?100241-52-9；
RN?100241-53-0；
RN?100241-54-1；
RN?100241-55-2；
RN 83773-90-4; And
RN?75842-08-9。
In another embodiment of the present invention, one group of general formula (I) chemical compound relates to following chemical compound, and wherein x and y are 1; J and K all are N independently; G is-C (R 4)=C (R 4)-; L and M are-N=; W is a chemical bond; R 2Be C 1-C 4Alkyl; R 3Be the phenyl that replaces, prerequisite is R 3Replaced by the substituent group beyond defluorination and the replacement De oxazolidine.
In another embodiment of the present invention, one group of general formula (I) chemical compound relates to following chemical compound, and wherein x is 1,2 or 3, and y is 1; J is N or C (R 10) and K be N; G is-C (R 4)=C (R 4)-; L and M all be independently-N=or-C (R 4)=, but prerequisite are that L and M are not-C (R simultaneously 4)=; W is-N (R 1) C (O)-,-C (O) N (R 1)-or-C (O)-; R 3Be selected from C 1-C 12Alkyl, aryl, C 1-C 12Heteroaryl, C 3-C 12Cyclic hydrocarbon radical, C 3-C 12Heterocyclic radical, have the multiring structure of 2 to 4 rings, wherein said ring is independently selected from cyclic hydrocarbon radical, heterocyclic radical, aryl and heteroaryl and wherein part or all of ring can condense each other; But prerequisite is R 2Be not C 1-6Alkyl, C 1-6Alkyl oxy and aryl C 1-6Alkyl.
In another embodiment of the present invention, one group of general formula (I) chemical compound relates to following chemical compound, and wherein G is-N (R 4)-or-C (R 4)=; L is-N (R 4)-and M be-N (R 4)-or-C (R 4)-.
The particular of the above-mentioned embodiment of the present invention is disclosed in the embodiment as described below of this paper.
In an embodiment, the method of the invention relates to by the The compounds of this invention administration with effective dose, treat and/or prevent by stearoyl-coa-desaturase (SCD), especially the disease of people SCD (hSCD) mediation, preferably relevant disease and lipid metabolic disorder with dyslipidemia, and especially be the disease relevant with the lipid level that raises, cardiovascular disease, diabetes, obesity, metabolism syndrome or the like.
The invention still further relates to the pharmaceutical composition that contains The compounds of this invention.In one embodiment, the present invention relates to contain the pharmaceutical composition of a certain amount of The compounds of this invention in drug acceptable carrier, the amount of this chemical compound is for working as animal, preferred mammal is most preferably effectively regulated triglyceride levels or treatment disease and the lipid metabolic disorder relevant with dyslipidemia during the human patients administration.In an embodiment of said composition, before compound administration of the present invention and before chemical compound of the present invention exists with the amount that can effectively reduce lipid level, the patient has the lipid level of rising, as triglyceride or the cholesterol that raises.
The effectiveness of The compounds of this invention and test
The present invention relates to this chemical compound of chemical compound, pharmaceutical composition and use and pharmaceutical composition treats and/or prevents by stearoyl-coa-desaturase (SCD), especially the method for the disease of people SCD (hSCD) mediation, be preferably disease relevant and lipid metabolic disorder with dyslipidemia, and especially relevant disease, especially cardiovascular disease, diabetes, obesity, metabolism syndrome or the like with the blood plasma lipide level that raises, by SDC regulator, the especially inhibitor of effective dose are implemented this method to patient's administration of this treatment of needs.
Usually, the invention provides treatment suffers from the patient of disease relevant with dyslipidemia and/or lipid metabolic disorder or prevents the patient to develop into the disease relevant with dyslipidemia and/or the method for lipid metabolic disorder, animal wherein, especially to exceed normal range (be abnormal lipid level to people's lipid level, as the blood plasma lipide level that raises), especially the level that is higher than normal level, preferred wherein said lipid is a fatty acid, as free or compound fatty acid, triglyceride, phospholipid or cholesterol, for example wherein the LDL-cholesterol levels be raise or the HDL-cholesterol levels reduce, or their combination in any, wherein said morbid state relevant with lipid or disease are the disease or the morbid state of SCD mediation, described method comprises the The compounds of this invention of treatment effective dose or the pharmaceutical composition that comprises The compounds of this invention animals administer, for example to mammal, especially human patients administration, wherein this chemical compound is regulated the SCD activity, the activity of preferred mediator SCD1.
The compounds of this invention is regulated, and preferably suppresses the activity of people SCD enzyme, the especially activity of people SCD1.
Adopt the analysis of describing among the embodiment 4 hereinafter, can determine that The compounds of this invention regulating, especially suppresses the general value in the SCD activity.Perhaps, can set up the general value of chemical compound in treatment disease and disease in the industrial standard animal model, described industrial standard animal model is used to prove that chemical compound is at the triglyceride or the cholesterol levels of treatment of obesity, diabetes or rising or be used to improve the effectiveness of glucose tolerance.This model comprises that the fat fa/fa rat of Zucker (can be from Harlan Sprague Dawley, Inc. (Indianapolis, Indiana) obtain), or Zucker diabetes obese rat (ZDF/GmiCrl-fa/fa) (can be from Charles River Laboratories (Montr é al Quebec) obtains).
Chemical compound of the present invention is the inhibitor of δ-9 desaturase and disease and the disease that can be used for treating the mankind and other organism, comprise that all that is caused by unusual δ-9 desaturase biological activity, maybe can be by regulating human diseases and the disease that δ-9 desaturase biological activity improves.
As herein defined, the disease or the morbid state of SCD mediation include but not limited to cardiovascular disease, dyslipidemia (includes but not limited to the serum triglyceride level disorder, hypertriglyceridemia, VLDL, HDL, LDL, fatty acid desaturation index (18: 1/18: 0 fatty acids for example, the perhaps ratio of other fatty acid of other place of this paper definition), cholesterol and T-CHOL, hypercholesterolemia and cholesterol disease (comprising the disease that is characterized as defective reverse cholesterol transport), familial combined hyperlipidemiam, coronary artery disease, atherosclerosis, heart disease, cerebrovascular disease (includes but not limited to apoplexy, cerebral infarction and transient ischemic attack (TIA)), Peripheral blood vessel disease and ischemic retinal disease, or associated disease or morbid state.In preferred embodiments, The compounds of this invention will improve patient's HDL level and/or triglyceride reducing level and and/or reduction LDL or non-HDL cholesterol levels.
Disease mediated or the morbid state of SCD comprises that also metabolism syndrome (includes but not limited to dyslipidemia, obesity and insulin resistant, hypertension, little albuminemia, hyperuricemia and high blood coagulation state), X syndrome, diabetes, insulin resistant, glucose tolerance is lowered, noninsulindependent diabetes, type ii diabetes, type i diabetes, diabetic complication, body weight (includes but not limited to obesity unusually, overweight, cachexia and apositia), lose weight, Body Mass Index and the disease relevant with leptin.In preferred embodiments, The compounds of this invention is used for the treatment of diabetes and obesity.
Term used herein " metabolism syndrome " is the clinical term of generally acknowledging that is used to describe morbid state, and this morbid state comprises the combination of abdominal circumference, hypertriglyceridemia, low HDL, hyperuricemia, high blood coagulation state and/or little albuminemia of type ii diabetes, glucose tolerance attenuating, insulin resistant, hypertension, obesity, increase.
The disease of SCD mediation or morbid state also comprise fatty liver, liver fat degeneration, hepatitis, non-alcoholic hepatitis, non-alcoholic stellato-hepatitis (NASH), alcoholic hepatitis, acute fatty liver, pregnancy fatty liver, drug-induced hepatitis, erythrohepatic protoporphyria (erythrohepatic protoporphyria), iron overload disease, hereditary hemochromatosis, hepatic fibrosis, liver cirrhosis, hepatocarcinoma and relative morbid state.
The disease or the morbid state of SCD mediation include but not limited to that also constitutional hypertriglyceridemia, supervention are in the hypertriglyceridemia of another disease or disease, unknown or do not indicate etiologic etiological hypertriglyceridemia, or associated disease or morbid state, described another disease or disease be hyperlipoproteinemia, familial histiocytic reticulosis's disease, lipoprotein lipase deficiency disease, apolipoprotein shortage (lacking or the ApoE shortage as ApoCII) etc. for example.
The disease or the morbid state of SCD mediation also comprise disease or the skin disorder that polyunsaturated fatty acid (PUFA) is unusual, and described skin disorder includes but not limited to eczema, acne, psoriasis, keloid cicatrization or prevention, with the generation of mucosa or such as relevant diseases of mucosa secretions such as monounsaturated fatty acid, wax esters.
The disease or the morbid state of SCD mediation also comprise inflammation, sinusitis, asthma, pancreatitis, osteoarthritis, rheumatoid arthritis, cystic fibrosis and premenstrual syndrome.
The disease or the symptom of SCD mediation also include but not limited to cancer, neoplasia, malignant tumor, transfer, tumor (optimum or pernicious), carcinogenesis, hepatocarcinoma etc., or associated disease or morbid state.
The disease of SCD mediation or morbid state comprise that also needs increase the morbid state of lean body mass or lean muscle quantities, for example need to strengthen the property by strong muscle.This paper also comprises myopathy and lipid myopathy, as Carnitine palmitoyltransferase deficiency disease (CPTI or CPTII).This treatment can be used for the mankind and animal husbandry, comprises cattle, pig or birds domestic animal or any other animals administer, with the generation of triglyceride reducing and/or provide thinner meat product and/or more healthy animal.
The disease or the morbid state of SCD mediation also comprise neurological disorder, psychiatric disorders, multiple sclerosis, ophthalmic and immune disorders, or associated disease or morbid state.
The disease or the morbid state of SCD mediation also comprise virus disease or viral infection, or associated disease or morbid state, described virus includes but not limited to all positive chain RNA virus, coronavirus, SARS virus, the coronavirus relevant with SARS, togavirus (Togaviruses), pico+ribonucleic acid+virus (Picornaviruses), Coxsackie virus, yellow fever virus, flaviviridae, α virus (Alphaherpesvirinae), it comprises rubella virus, eastern equine encephalitis virus, western equine encephalitis virus, Venezuelan equine encephalitis virus, the sindbis virus, Semliki Forest virus, datum hole Kenya virus, Ou Liwengniweng-Ni Weng virus (O ' nyong ' nyongvirus), ross river virus, Mayaro virus, α virus; Astroviridae, it comprises Astrovirus, human astrovirus virus; Calicivirus section, it comprises pig vesicular exanthema virus, Norwalk virus, calicivirus, cattle calicivirus, pig calicivirus, hepatitis E; Coronaviridae, it comprises coronavirus, SARS virus, avian infectious bronchitis virus, bovine coronavirus, canine coronavirus, feline infectious peritonitis virus, human corona virus 299E, human corona virus OC43, murine hepatitis virus, Porcine epidemic diarrhea virus, pigs haemagglutinating encephalomyelitis virus, transmissible gastroenteritis of swine virus, rat coronavirus, turkey coronavirus, rabbit coronavirus, berne virus, background of cloth da virus; Flaviviridae, it comprises hepatitis C virus, west nile virus, yellow fever virus, Saint Louis' encephalitis virus, dengue fever belongs to, hepatitis G virus, epidemic encephalitis B virus, Austrian X-disease virus, Central European TBE virus, far east tick-borne encephalitis virus, Kyasanur forest virus, louping-ill virus, Bo Wasang virus, msk haemorrhagia fever virus, Kumilinge virus, Absetarov anzalova hypr virus, ilheus virus, sieve Theo encephalitis, Langat virus, Pestivirus, bovine viral diarrhoea, swine fever virus, Rio Bravo belongs to, Tyuleniy belongs to, Ntaya belongs to, Uganda S belongs to, Modoc belongs to; Picornaviridae, it comprises Coxsackie A disease poison, rhinovirus, hepatitis A virus, encephalomyocarditis virus, encephalomyocardis virus, ME virus, human poliovirus 1, Coxsackie B virus; Marmor upsilon section, it comprises marmor upsilon, ryegrass mosaic virus, Fructus Hordei Vulgaris yellow mosaic virus.In addition, can also be by hepatitis virus, hepatitis B virus, hepatitis C virus, HIV (human immunodeficiency virus) (HIV) disease that cause or associated or infection.Medicable viral infection comprises the viral infection (hepatitis or HIV) of virus use RNA intermediate as a replicative cycle part; In addition, can also be by emitting such as influenza and RNA negative strand viruses disease that cause or associated or infection such as parainfluenza virus.
The chemical compound that identifies in this description is by realizing suppressing the desaturation (for example C9-C10 desaturation of stearoyl-coa) of multiple fatty acid such as stearoyl-coa-desaturase 1 δ-9 desaturases such as (SCD1).Similarly, these chemical compounds suppress the generation of multiple fatty acid and downstream metabolites thereof.This may cause the accumulating of other upstream precursor of stearoyl-coa or palmityl CoA and multiple fatty acid, and this may cause negative feedback loop, causes that fatty acid metabolism all changes.Any the possibility of result among these results finally is provided by the wholistic therapy benefit that is provided by chemical compound.
Usually, successful SCD suppression therapy agent will be satisfied part or all of following standard.Oral availability should be equal to or greater than 20%.Animal model usefulness is less than about 2mg/Kg, 1mg/Kg or 0.5mg/Kg, and the human dosage of target is 50 to 250mg/70Kg, but the dosage that exceeds this scope also is to accept (" mg/Kg " refers to every kilogram of milligram chemical compound that carries out the administration whose body weight).Therapeutic index (or ratio of toxicity dose and therapeutic dose) should be greater than 100.Tire (with IC 50Value representation) should be lower than 10 μ M, preferably be lower than 1 μ M, and most preferably be lower than 50nM.IC 50(" inhibition concentration-50% ") is in the SCD biological activity is analyzed, and reaches the measured value of the required chemical compound amount of the active inhibition of 50%SCD in the specific period.Measure the SCD enzymatic activity, any method of preferred mice or people SCD enzymatic activity all can be used for analyzing the activity of chemical compound in suppressing described SCD activity of using in the inventive method.In 15 minutes microsomes were analyzed, The compounds of this invention showed IC 50Preferably be lower than 10 μ M, be lower than 5 μ M, be lower than 2.5 μ M, be lower than 1 μ M, be lower than 750nM, be lower than 500nM, be lower than 250nM, be lower than 100nM, be lower than 50nM, and most preferably be lower than 20nM.The compounds of this invention can show reversible inhibition (being competitive inhibition), and does not preferably suppress other iron-binding protein.Required administration preferably should not surpass makes an appointment with once or twice or is no more than the number of times of having a dinner every day.
SCD enzyme and microsome analytical procedure that people such as use Brownlie describe in the supra. document can easily be finished the evaluation of The compounds of this invention as the SCD inhibitor.When in this analysis, testing, concentration in test compounds is under the 10 μ M, The compounds of this invention has and is lower than 50% residue SCD activity, preferably the concentration in test compounds is under the 10 μ M, have and be lower than 40% residue SCD activity, and more preferably the concentration in test compounds is to have under the 10 μ M to be lower than 30% residue SCD activity, and even be to have under the 10 μ M to be lower than 20% residue SCD activity more preferably in the concentration of test compounds, therefore show that The compounds of this invention is the active effective inhibitor of SCD.
These results provide the foundation for the structure activity relationship (SAR) between analytical test chemical compound and the SCD.Some R group tends to provide more effective inhibition chemical compound.It is one of instrument of those skilled in the art that SAR analyzes, and can be used for nowadays differentiating that The compounds of this invention is used as the preferred embodiment that therapeutic agent uses.
Other method of testing chemical compound disclosed herein also obtains for those skilled in the art easily.Thereby, in addition, can finish described contact in vivo.In such embodiment, by with described chemical agent to suffering from the animals administer with triglyceride (TG) or very low density lipoprotein (VLDL) (VLDL) associated conditions, and detect the variation of the plasma triglyceride level of described animal subsequently, thereby identify the therapeutic agent that can be used for treatment and triglyceride (TG) or very low density lipoprotein (VLDL) (VLDL) associated conditions, with the contact described in the completing steps (a).In this embodiment, described animal can be human, for example suffers from the human patients of this disease and the described disease of needs treatment.
In the particular of method, the active described variation of the SCD1 of described animal is active the reduction in this body, and preferred wherein said SCD1 regulator does not suppress the biological activity of δ-5 desaturase, δ-6 desaturase or fatty acid synthetase basically.
The model system that is used for the chemical compound evaluation can include but not limited to the use of hepatomicrosome, for example from the hepatomicrosome of the mice of keeping with high carbohydrate diet, or from the hepatomicrosome of the human donor that comprises the people who suffers from obesity.Can also use immortal cell line, for example HepG2 (from human liver), MCF-7 (from human breast cancer) and 3T3-L1 (from the mice lipocyte).Also can use such as primary cell lines such as mice primary hepatocytes with the test The compounds of this invention.When using whole animal, also can use mice as the primary hepatocyte source, wherein said mice is kept to increase the active and/or raising plasma triglyceride level (promptly 18: 1/18: 0 ratios) of SCD in the microsome with high carbohydrate diet; Perhaps can use the mice of feeding normal meals or have the mice of normal triglyceride levels.Use also can be used as mice phenotype group data base at the mouse model of the transgenic mice of hypertriglyceridemia design.Rabbit and hamster also can be used as animal model, especially express the animal model of CEPT (cetp).
Another appropriate method of determining the interior effectiveness of body of The compounds of this invention is to measure its influence to the SCD enzyme inhibition indirectly by measuring individual desaturation index behind described compound administration." the desaturation index " that uses in this description refers to product and ratio from the measured SCD zymolyte of given tissue sample.Can use three kinds of different equation 18: 1n-9/18: 0 (oleic acid is than stearic acid); 16: 1n-7/16: 0 (palmitoleic acid is than Palmic acid); And/or 16: 1n-7+18: 1n-7/16: 0 (the total overall reaction product that measuring goes to satisfy at 16: 0 acts on and the ratio of 16: 0 substrates) calculates this index.Mainly in liver or plasma triglyceride, measure the desaturation index, but also can in other selected lipid part, measure from multiple tissue.In general, the desaturation index is the instrument that is used for the plasma adiponectin mass spectrum.
Many human diseasess and disease are the unusual bioactive results of SCD1, and therapeutic agent that can the application of the invention is regulated the SCD1 biological activity and is improved.
The inhibition that SCD expresses can also influence the generation or the level of fatty acid composition and the triglyceride and the cholesteryl ester of membrane phospholipid.The fatty acid of phospholipid is formed the flowability of final decision film, and can influence the metabolism and the obesity of lipoprotein to the effect of triglyceride and cholesteryl ester composition.
In carrying out operation of the present invention, certainly can understand the special buffer, medium, reagent, cell, condition of culture etc. of indication and unrestricted, and it should be interpreted as and comprise that those of ordinary skills think paid close attention to down or valuable all the relevant materials of the specific background of discussing herein.For example, can use a kind of buffer system or culture medium to replace another kind of buffer system or culture medium usually, and still can reach result similar but inequality.Those skilled in the art have enough knowledge and the methodology about this system, thereby need not undo experimentation and just can carry out such purpose of using method disclosed herein and operation to be reached to realize best that substitutes.
Pharmaceutical composition of the present invention and administration
The invention still further relates to the pharmaceutical composition that contains The compounds of this invention disclosed herein.In one embodiment, the present invention relates in drug acceptable carrier, contain the compositions of a certain amount of The compounds of this invention, described amount is for working as animal, preferably to mammal, during most preferably to the human patients administration, this chemical compound is effectively regulated triglyceride levels or treatment disease and the lipid metabolic disorder relevant with dyslipidemia.In an embodiment of said composition, before compound administration of the present invention and The compounds of this invention existed with the amount of the described lipid level of effective reduction, described patient had the lipid level of rising, for example triglyceride of Sheng Gaoing or cholesterol.
Pharmaceutical composition used herein also contains the medicine acceptable carrier that comprises any suitable diluent or excipient, described medicine acceptable carrier comprises itself does not induce the medicament of generation to the individual deleterious antibody of accepting described compositions, and can administration and do not have unsuitable toxicity.The medicine acceptable carrier includes but not limited to liquid, for example water, saline, glycerol and ethanol etc.Among the REMINGTON ' S PHARMACEUTICAL SCIENCES (Mack Pub.Co., N.J.current edition) going through of medicine acceptable carrier, diluent and other excipient arranged.
Those skilled in the art will know that the suitable dosage of the chemical compound that how to be identified for treating disease that this paper pays close attention to and disease.Usually based on the primary evidence of zooscopy, determine therapeutic dose by research about the mankind's dosage range.Dosage must be enough to reach the desired therapeutic effect and don't the patient be caused the side effect of not expecting.For animal, the preferred dose scope is 0.001mg/Kg to 10, and 000mg/Kg comprises 0.5mg/Kg, 1.0mg/Kg and 2.0mg/Kg, but the dosage that exceeds this scope remains acceptable.Dosage regimen can be once a day or twice, but more or less administration number of times also is gratifying.
Those skilled in the art are to determining medication (oral, vein, suction, subcutaneous etc.), dosage form, suitable drug excipient and also being familiar with other the relevant material that chemical compound is delivered to the individuality that needs treatment.
In another purposes of the present invention, for the contrast purpose, can be used for external as exemplary agents chemical compound of the present invention or body in study, also can be used for treating or preventing other chemical compound of multiple disease disclosed herein to seek.
The preparation of The compounds of this invention
Should be appreciated that in the following description to have only when the variant of substituent combination and/or described general formula can obtain stable chemical compound, the variant of substituent combination of this class and/or described general formula is only permission.
It will be understood by those skilled in the art that in the described method of infra that the functional group of midbody compound may need by suitable protecting group protection.Such functional group comprises hydroxyl, amino, sulfydryl and carboxylic acid.Suitable hydroxyl protecting group comprises trialkylsilkl or alkyl diaryl silicyl (for example t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethyl silyl), THP trtrahydropyranyl, benzyl or the like.Suitable amino, miaow base and guanidine radicals protecting group comprise tert-butoxycarbonyl, benzyloxycarbonyl or the like.Suitable sulfhydryl protected base comprises-C (O)-R " (wherein R " be alkyl, aryl or aralkyl), to methoxy-benzyl, trityl etc.Suitable carboxylic acid protecting group comprises alkyl, aryl or aralkyl esters.
Can introduce or remove protecting group according to well known to a person skilled in the art with standard technique described herein.
Green, T.W. and P.G.M.Wutz, Protective Groups in Organic Synthesis (protecting group in the organic synthesis) (1999), 3rd Ed. has described the purposes of protecting group in detail among the Wiley.Described protecting group can also be a fluoropolymer resin, for example Wang resin or 2-chlorine trityl chloride resin.
Though those skilled in the art are further appreciated that these protected derivants itself of The compounds of this invention and may have pharmaceutically active, with its to the mammal administration and subsequently in vivo metabolism have the The compounds of this invention of pharmaceutically active with formation.Therefore, such derivant can be referred to as " prodrug ".All prodrugs of The compounds of this invention all are included in the scope of the present invention.
Following reaction scheme has illustrated the method for preparing chemical compound of the present invention.Should be appreciated that those skilled in the art can prepare these chemical compounds by similar method or by method known to those skilled in the art.Usually, can be by such as Sigma Aldrich, Lancaster Synthesis, Inc.,, sources such as Maybridge, Matrix Scientific, TCI and Fluorochem USA obtain starting ingredient, perhaps synthesize starting ingredient (for example referring to Advanced Organic Chemistry:Reactions according to source well known by persons skilled in the art, Mechanisms, and Structure (Advanced Organic Chemistry: reaction, mechanism and structure), 5th edition (Wiley, December2000)), perhaps prepare starting ingredient as described herein.Unless clearly definition is arranged in addition, R 1, R 2, R 3, R 4, R 5, R 5a, R 6, R 6a, R 7, R 7a, R 8And R 8aDefinition in following reaction scheme is all as the definition in this explanation.PG represents protecting group, as BOC, benzyl etc.
Those skilled in the art also can be by preparing chemical compound of the present invention with the following similar method of method described in open:
The disclosed patent application WO 03/076400 of PCT;
The disclosed patent application WO 03/066604 of PCT;
The disclosed patent application WO 01/019822 of PCT;
The disclosed patent application WO 99/021834 of PCT;
The disclosed patent application WO 99/020606 of PCT;
The disclosed patent application WO 98/001446 of PCT;
The disclosed patent application WO 94/012495 of PCT;
No. 0 300 526, the disclosed patent application in Europe;
No. 0 156 433, the disclosed patent application in Europe;
No. 0 055 583, the disclosed patent application in Europe;
No. 0 009 655, the disclosed patent application in Europe;
United States Patent (USP) the 5th, 719, No. 154; And
United States Patent (USP) the 5th, 494, No. 908.
Usually, can be according to synthetic general formula of the present invention (I) chemical compound of the general operation described in the following reaction scheme 1, wherein L and M are-N=, and G is-C (R 4)=C (R 4)-and W be-N (R 1) C (O)-.Should be appreciated that to prepare other chemical compound shown in the general formula (I) in a similar manner that wherein L, M, G and W are all as defined in the above-mentioned summary of the invention.
Reaction scheme 1
Figure A20058003978700441
The parent material of above-mentioned reaction scheme can commerce be buied or can be prepared according to method known to those skilled in the art, or by method preparation disclosed herein.Usually, be prepared as follows chemical compound of the present invention according to above-mentioned reaction response scheme:
Can use oxidant that methyl pyridazine compound 101 is oxidized to carboxylic acid 102 by in the presence of acid such as, but not limited to concentrated sulphuric acid such as, but not limited to potassium dichromate.In solvent such as, but not limited to dichloromethane, in the presence of such as but not limited to the alkali of diisopropylethylamine, 1-hydroxyl-1H-benzotriazole and 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide, by forming amide 103 by carboxylic acid 102 with suitable amine reaction.Perhaps, can react by 102 chloride derivative and suitable amine and prepare amide 103.This reaction can be carried out in such as, but not limited to the solvent of dichloromethane in the presence of the alkali such as, but not limited to diisopropylethylamine.Chlorine pyridazine compound 103 obtains chemical compound 105 with piperazine 104 reaction in the acetonitrile that refluxes.1, the tetrabutylammonium iodide of 8-diazabicyclo [5.4.0] 11 carbon-7-alkene and catalytic amount exists down, obtains end product 106 by diethylenediamine compound 105 and heteroaromatic halide reaction in such as, but not limited to the solvent of diox.Perhaps, can be under Buchwald/Hartwig amination condition by 105 with suitable aryl halide prepared in reaction chemical compound 106 (for example see people such as Buchwald, S.L., J.Org.Chem.2000, 65, 1158).
Perhaps, can be under condition well known by persons skilled in the art, make 104 with heteroaromatic halogenide or heteroaromatic amine reaction, by 104 preparation diethylenediamine compounds 107.1, the tetrabutylammonium iodide of 8-diazabicyclo [5.4.0] 11 carbon-7-alkene and catalytic amount exists down, and such as, but not limited to N, in the solvent of dinethylformamide, 107 can obtain end product 106 equally with the coupling of chlorine pyridazine compound 103.
Though any those skilled in the art can prepare The compounds of this invention according to disclosed current techique above, for convenience's sake, be provided in other place of this description about more details of the synthetic technology of The compounds of this invention.And used all reagent and reaction condition all is known in those skilled in the art in synthesizing, and can or get from general commercial source.
Preparation 1
Synthesizing of 3-piperazine-1-base benzo [d] isothiazole
In 125 ℃ of oil baths, (2.75g, 32mmol) (1.00g, mixture 5.80mmol) heated in sealed tube 24 hours with 3-chloro-benzo [d] isothiazole with Piperazine anhydrous.Then with frozen water with the quenching of orange fused mass, and once add 50%NaOH.Use the dichloromethane extraction mixture, obtain crude product, can obtain the title compound of faint yellow solid, yield 24% (0.260g) by recrystallization with the crude product purification.MS(ES+)m/z220(M+1)。
Preparation 2
Synthesizing of 6-chlorine pyridazine-3-carboxylic acid (2-cyclopropyl ethyl) amide
A. the potassium dichromate (55.40g) that in the 140mL concentrated sulphuric acid mechanical agitation solution of 3-chloro-6-methyl pyridazine (155.6mmol), slowly adds fine powdered, and with temperature maintenance below 50 ℃.After interpolation is finished, under 50 ℃, continue again to stir 4 hours.Again with heavy-gravity bottle green liquid cools and add trash ice carefully.With ethyl acetate (6 * 400mL) extractive reaction mixture.The combined ethyl acetate extract is used anhydrous Na 2SO 4Dry.The vacuum concentration solvent obtains pale red 6-chlorine pyridazine-3-carboxylic acid (106.6mmol).This material just is used for next step reaction without being further purified.Yield 69%.M.p.145 ℃ (decomposition). 1H?NMR(300MHz，DMSO-d 6)δ13.1，8.20，8.05。
B. in blanket of nitrogen and under the ambient temperature, in dichloromethane (95mL) solution of 6-chlorine pyridazine-3-carboxylic acid (15.8mmol), add diisopropylethylamine (46.7mmol), I-hydroxybenzotriazole monohydrate (23.7mmol) and 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide (23.7mmol).The gained mixture was stirred 15 minutes, and add 2-cyclopropyl ethamine (20.2mmol).After stirring 36 hours at ambient temperature,, then wash and use anhydrous Na with water with dichloromethane (100mL) diluted reaction mixture 2SO 4Dry.Vacuum is removed solvent.By column chromatography (hexane that contains 30% ethyl acetate) purification, obtain title compound (8.70mmol).Yield 55%.
Preparation 3
Synthesizing of 6-piperazine-1-radical pyridazine-3-carboxylic acid (2-cyclopropyl ethyl) amide
(1.48g is 17.2mmol) with 6-chlorine pyridazine-3-carboxylic acid (2-cyclopropyl ethyl) amide (1.29g, acetonitrile 5.73mmol) (60mL) mixture reflux 16 hours to make piperazine.After the reactant mixture cooling, with the gluing material of dichloromethane (50mL) dilution, (MgSO is used in 2 * 20mL) washings to water 4Dry.After the filtration, vacuum concentrated filtrate.By column chromatography, with dichloromethane (100%), use methanol then: dichloromethane (1: 9) carries out eluting and comes the thick material of purification, and obtaining 1.18g (75%) is solid title product.
By synthesizing of (but being not limited to) following examples exemplary illustration The compounds of this invention.
Embodiment 1
6-[4-(4-fluorophenyl) piperazine-1-yl] pyridazine-3-carboxylic acid (2-cyclopropyl ethyl) amide synthetic
1, and 8-diazabicyclo [5.4.0] 11 carbon-7-alkene (DBU) (0.23mL, 1.54mmol) and tetrabutylammonium iodide (Bu 4NI) (11mg, under existence 0.0298mmol), (0.117g 0.638mmol) handles 6-chlorine pyridazine-3-carboxylic acid (2-cyclopropyl ethyl) amide (0.120g, DMF 0.532mmol) (2.3mL) solution with 1-(4-fluorophenyl) piperazine.Reactant mixture was heated 15 hours down at 75 ℃ to 80 ℃, be cooled to room temperature, with ethyl acetate (100mL) dilution.Water (3 * 10mL), saline (3 * 10mL) washing organic layers, use Na 2SO 4Dry also vacuum concentration.By the column chromatography purification crude product, obtain the title compound of white powder, yield 74% (0.146g). 1H?NMR(300MHz，CDCl 3)δ8.05-7.99(m，2H)，7.02-6.89(m，5H)，3.90(t，J＝5.2Hz，4H)，3.55(m，2H)，3.23(t，J＝5.2Hz，4H)，1.55-1.47(m，2H)，0.79-0.72(m，1H)，0.49-0.43(m，2H)，0.11-0.06(m，2H).MS(ES+)m/z370.3(M+1)。
Embodiment 1.1
Synthesizing of 6-(4-benzo [d] isothiazole-3-base piperazine-1-yl) pyridazine-3-carboxylic acid (2-cyclopropyl ethyl) amide
Adopt the operation of describing among the embodiment 1, the change of being done only is to substitute 1-(4-fluorophenyl) piperazine with 3-piperazine-1-base benzo [d] isothiazole to come and the reaction of 6-chlorine pyridazine-3-carboxylic acid (2-cyclopropyl ethyl) amide, obtain the title compound of white powder, yield 25% (0.0307g). 1H?NMR(300MHz，CDCl 3)δ8.13(d，J＝9.5Hz，1H)，7.94(m，2H)，7.80(d，J＝8.0Hz，1H)，7.50(t，J＝7.3Hz，1H)，7.38(t，J＝7.8Hz，1H)，7.16(d，J＝8.0Hz，1H)，4.05(m，4H)，3.73(m，4H)，3.51(m，2H)，1.50(m，2H)，0.73(m，1H)，0.45(m，2H)，0.06(m，2H).MS(ES+)m/z409(M+1)。
Embodiment 1.2
6-[4-(3-5-flumethiazine-2-yl) piperazine-1-yl] pyridazine-3-carboxylic acid (2-cyclopropyl ethyl) amide synthetic
Adopt the operation of describing among the embodiment 1, the change of being done only is to substitute 1-(4-fluorophenyl)-piperazine with 1-(3-5-flumethiazine-2-yl) piperazine to come and the reaction of 6-chlorine pyridazine-3-carboxylic acid (2-cyclopropyl ethyl) amide, obtain the title compound of white powder, yield 43% (0.061g). 1HNMR(300MHz，CDCl 3)δ8.44(m，1H)，8.01(m，2H)，7.89(m，1H)，7.02(s，2H)，3.88(m，4H)，3.54(m，2H)，3.41(m，4H)，1.51(m，2H)，0.78(m，1H)，0.45(m，2H)，0.07(m，2H).MS(ES+)m/z421(M+1)。
Embodiment 1.3
Synthesizing of 6-(4-pyridine-2-base piperazine-1-yl) pyridazine-3-carboxylic acid (2-cyclopropyl ethyl) amide
Adopt the operation of describing among the embodiment 1, the change of being done only is to substitute 1-(4-fluorophenyl)-piperazine with 1-pyridine-2-base piperazine to come and the reaction of 6-chlorine pyridazine-3-carboxylic acid (2-cyclopropyl ethyl) amide, obtain the title compound of white powder, yield 30% (0.036g). 1HNMR(300MHz，CDCl 3)δ8.19(m，1H)，8.01(m，1H)，7.50(m，1H)，7.00(d，J＝9.9Hz，1H)，6.67(m，2H)，3.89(m，4H)，3.75(m，4H)，3.54(m，2H)，1.50(m，2H)，0.74(m，1H)，0.45(m，2H)，0.09(m，2H). 13C?NMR(75MHz，CDCl 3)δ163.2，160.2，158.9，147.9，144.9，137.8，126.9，113.8，112.1，107.2，44.6，39.6，34.6，8.67，4.25.MS(ES+)m/z353.6(M+1)。
Embodiment 1.4
6-[4-(3-trifluoromethyl)-piperazine-1-yl] pyridazine-3-carboxylic acid (2-cyclopropyl ethyl) amide synthetic
Adopt the operation of describing among the embodiment 1, the change of being done only is to substitute 1-(4-fluorophenyl)-piperazine with 1-(3-trifluoromethyl) piperazine to come and the reaction of 6-chlorine pyridazine-3-carboxylic acid (2-cyclopropyl ethyl) amide, obtain the shape title compound of white powder, yield 57% (0.210g). 1H NMR (300MHz, CDCl 3) δ 8.09 (d, J=9.5Hz, 1H), 7.98 (t, J=5.4Hz, 1H), 7.38 (t, J=7.5Hz, 1H), 7.12 (m, 3H), 7.04 (d, J=9.5Hz, 1H), 3.96 (m, 4H), 3.55 (m, J=6.72 and 13.2Hz, 2H), 3.40 (m, 4H), 1.51 (dd, J=6.7 and 13.8Hz, 2H), 0.74 (m, 1H), 0.45 (m, 2H), 0.08 (m, 2H). 13CNMR (75MHz, CDCl 3) δ 162.9,150.8,145.2,129.8,127.2,119.19,116.75,112.6,48.5,44.7,39.7,34.5,8.7,4.2.
Embodiment 2
Synthesizing of 6-(4-benzoxazole-2-base-piperazine-1-yl) pyridazine-3-carboxylic acid (2-cyclopropyl ethyl) amide
To 6-piperazine-1-base-pyridazine-3-carboxylic acid (2-cyclopropyl ethyl) amide (0.080g, 0.290mmol add 2-Lv benzoxazole (0.053g in the) De diox (7mL), 0.34mmol), then add 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene (0.132mL, 0.87mmol) and tetrabutylammonium iodide (3mg).Made the reactant mixture stirring at room 3 hours.Vacuum is removed solvent.Residue is dissolved in the ethyl acetate, then with citric acid, sodium bicarbonate and saline solution washing.Separate organic layer, use anhydrous Na 2SO 4Drying, and evaporation.Residue carries out purification by recrystallization from normal hexane, obtain the title compound of white powder, yield 44% (0.050g). 1HNMR(300MHz，CDCl 3)δ8.07(d，J＝9.5Hz，1H)，7.99(t，J＝5.3Hz，1H)，7.39(d，J＝7.4Hz，1H)，7.28(d，J＝7.8Hz，1H)，7.19(m，1H)，7.05(m，2H)，3.92(m，8H)，3.55(m，2H)，1.48(m，2H)，0.79(m，1H)，0.46(m，2H)，0.07(m，2H).MS(ES+)m/z393(M+1)。
Embodiment 2.1
Synthesizing of 6-(4-benzothiazole-2-base-piperazine-1-yl) pyridazine-3-carboxylic acid (2-cyclopropyl ethyl) amide
Adopt the operation of describing among the embodiment 2, the change of being done only is to substitute 2-Lv benzoxazole with the 2-chloro benzothiazole to come and the reaction of 6-piperazine-1-radical pyridazine-3-carboxylic acid (2-cyclopropyl ethyl) amide, obtain the title compound of white powder, yield 27% (0.040g). 1H?NMR(300MHz，CDCl 3)δ8.07(d，J＝9.5Hz，1H)，7.99(t，J＝5.4Hz，1H)，7.59(m，2H)，7.32(t，J＝6.5Hz，1H)，7.12(t，J＝8.2Hz，1H)，7.03(d，J＝9.4Hz，1H)，3.94(m，4H)，3.81(m，4H)，3.53(m，2H)，1.50(m?2H)，0.75(m，1H)，0.45(m，2H)，0.06(m，2H).MS(ES+)m/z409.2(M+1)。
Embodiment 2.2
Synthesizing of 6-(4-quinazoline-4-base piperazine-1-yl) pyridazine-3-carboxylic acid (2-cyclopropyl ethyl) amide
Adopt the operation of describing among the embodiment 2, the change of being done only is to substitute 2-Lv benzoxazole with the 4-chloro-quinazoline to come and the reaction of 6-piperazine-1-radical pyridazine-3-carboxylic acid (2-cyclopropyl ethyl) amide, obtain the title compound of white powder, yield 27% (40mg). 1H?NMR(300MHz，CDCl 3)δ8.76(s，1H)，8.06(d，J＝9.4Hz，1H)，7.95(m，3H)，7.77(t，J＝7.3Hz，1H)，7.50(t，J＝7.3Hz，1H)，7.01(d，J＝9.5Hz，1H)，3.98(m，8H)，3.55(m，2H)，1.5(m，2H)，0.74(m，1H)，0.43(m，2H)，0.08(m，2H).MS(ES+)m/z403.67(M+1)。
Embodiment 3
6-[4-(3-oxo-3H-iso-indoles-1-yl) piperazine-1-yl] pyridazine-3-carboxylic acid (2-cyclopropyl ethyl) amide synthetic
Iso-indoles-(0.292g, 2.00mmol) (0.825g's 1-ketone together 3.00mmol) seethed with excitement 48 hours in ethanol (20mL) with 6-piperazine-1-radical pyridazine-3-carboxylic acid (2-cyclopropyl ethyl) amide with 3-amino.Vacuum concentrated solution.This residue carries out purification by column chromatography.Obtain the title compound of white solid, yield 40% (0.328g). 1H NMR (300MHz, CDCl 3) δ 8.07 (d, J=9.5Hz, 1H), 7.97 (t, J=5.8Hz, 1H), 7.76 (d, J=7.0Hz, 1H), 7.64 (d, J=7.3Hz, 1H), 7.52 (m, 1H), 7.01 (d, J=9.5Hz, 1H), 4.42-4.35 (m, 4H), and 4.23-4.20 (m, 2H), 3.93-3.89 (m, 2H), 3.54 (dd, J=6.7 and 13.2Hz, 1H), 1.49 (m, 1H), 0.79-0.66 (m, 1H), 0.47-0.41 (m, 2H), 0.10-0.05 (m, 2H). 13C NMR (75MHz, CDCl 3) δ 181.5,174.6,162.9,159.6,145.6,138.1,134.9,132.5,131.7,127.3,124.0 123.3,112.2,47.2,46.4 44.5,43.2,39.7,34.5,8.7,4.2.MS (ES+) m/z405.1 (M+1).
Embodiment 4
The stearoyl-coa-desaturase that uses the Mouse Liver microsome to measure test compounds suppresses active
Microsome analytical method described in people's such as use SCD enzyme and Brownlie the PCT publication application WO 01/62954 can easily be implemented the evaluation of The compounds of this invention as the SCD inhibitor.
The MC preparation of Mouse Liver
The male ICP mice with Hi CHO low-fat diet feed through slight halothane (containing 15% halothane in the mineral oil) anesthesia makes its death by blood-letting during enzymatic activity high.Use cold 0.9%NaCl solution washing liver immediately, weigh and shred with shears.Except as otherwise noted, all operations all carries out under 4 ℃.Liver is being contained 0.25M sucrose, 62mM kaliumphosphate buffer (pH7.0), 0.15M KCl, 1.5mM N-acetylcysteine, 5mM MgCl 2(1: 3w/v), the Potter-Elvehjem Potter-Elvehjem Tissue Grinders that adopts 4 strokes is with liver homogenateization with the solution of 0.1mMEDTA.With homogenate under 10,400 * g centrifugal 20 minutes to remove degranulation line body and cell debris.Supernatant was through 3-layer filtered through gauze and under 105,000 * g centrifugal 60 minutes.With little glass/special teflon pressure-even pulp crusher make the microsome pellet lentamente resuspending in identical homogenization solution, and be stored under-70 ℃.There is not a line body pollution in evaluation through enzyme.Use hyclone albumen as the canonical measure protein concentration.
Hatch the mouse liver microsome with test compounds
By being joined, the 2mg microsomal protein contains 0.20 μ Ci substrate fatty acid (1- 14The C Palmic acid) makes in the preincubate pipe and begin reaction, the ultimate density of microsomal protein in 1.5ml homogenization solution is 33.3 μ M, and this homogenization solution contains the test compounds of 42mM NaF, 0.33mM nicotiamide, 1.6mMATP, 1.0mM NADH, 0.1mM coenzyme A and 10 μ M concentration.This test tube is the spiral type vibration tempestuously, and hatch 15 minutes in shaking bath (37 ℃) after, cessation reaction is also analyzed fatty acid.
Following analysis fatty acid: make the reactant mixture saponification with 10%KOH, obtain free fatty acid, and in methanol, use BF 3It is further methylated.Use Hewlett Packard 1090, Series II chromatograph is analyzed fatty acid methyl ester by high performance liquid chromatography (HPLC), this chromatograph be equipped with the diode array detector that is set in 205nm, have solid flicker box (for 14C-detects, efficient is 97%) radioisotope detector (Model 171, Beckman, CA), and anti-phase ODS (C-18) Beckman post (250mm * 4.6mm id. that is connected with the pre-column that has μ Bondapak C-18 (Beckman) insert; Granularity μ m).With the flow velocity of 1ml/min, the usefulness acetonitrile/water (95: 5v/v) methyl ester such as separation of fatty acids such as degree such as grade, and by relatively identifying with safe criterion.Perhaps, can pass through capillary column gas chromatography (GC) or thin layer chromatography (TLC) and analyze fatty acid methyl ester.
It will be understood by a person skilled in the art that and to carry out multiple modification that these modifications can be used for measuring test compounds to the active inhibition of the stearoyl-coa-desaturase in the microsome to this analysis.
When testing in this analysis, representative compounds of the present invention has shown the activity as the SCD inhibitor.Activity is defined as the percentage ratio of remaining SCD enzymatic activity under the expectation concentration of test compounds.
This paper with mention in this description and/or the request for data table in the full content of listed all United States Patent (USP)s, U.S. Patent Application Publication, U.S. Patent application, foreign patent, foreign patent application and non-patent publications be incorporated herein by reference.
By understanding in aforementioned,, can carry out various modifications under condit without departing from the spirit and scope of the present invention though described specific embodiments of the present invention for the exemplary illustration purpose.Therefore, the present invention only is subjected to the restriction of claims.

Claims (17)

1. suppress the active method of human stearoyl-coa-desaturase (hSCD), it comprises the hSCD source is contacted with general formula (I) chemical compound,
Figure A2005800397870002C1
Wherein:
X and y all are 0,1,2 or 3 independently;
G is-N (R 4)-,-O-,-S (O) t-(wherein t is 0,1 or 2) ,-C (R 4)=or-C (R 4)=C (R 4)-;
J and K all are N or C (R independently 10);
L and M all independently be-N=,-N (R 4)-or-C (R 4)=, but prerequisite are to be-C (R as G 4)=or-C (R 4)=C (R 4)-time, L and M are not-C (R simultaneously 4)=;
W be chemical bond ,-N (R 1) C (O)-,-C (O) N (R 1)-,-OC (O) N (R 1)-,-N (R 1) C (O) N (R 1)-,-O-,-N (R 1)-,-S (O) t-(wherein t is 0,1 or 2) ,-N (R 1) S (O) p-(wherein p is 1 or 2) ,-S (O) pN (R 1)-(wherein p be 1 or 2) ,-C (O)-,-OS (O) 2N (R 1)-,-OC (O)-,-C (O) O-or-N (R 1) C (O) O-;
Each R 1Be independently selected from hydrogen, C 1-C 12Alkyl, C 2-C 12Hydroxyalkyl, C 4-C 12Cyclic hydrocarbon radical alkyl and C 7-C 19Aralkyl;
R 2Be selected from C 1-C 12Alkyl, C 2-C 12Thiazolinyl, C 2-C 12Hydroxyalkyl, C 2-C 12Hydroxy alkenyl, C 2-C 12Alkoxyalkyl, C 3-C 12Cyclic hydrocarbon radical, C 4-C 12Cyclic hydrocarbon radical alkyl, aryl, C 7-C 19Aralkyl, C 3-C 12Heterocyclic radical, C 3-C 12Heterocyclic radical alkyl, C 1-C 12Heteroaryl and C 3-C 12Heteroaryl alkyl;
Or R 2For having the multiring structure of 2 to 4 rings, wherein said ring is independently selected from cyclic hydrocarbon radical, heterocyclic radical, aryl and heteroaryl, and wherein part or all of described ring can condense each other;
R 3Be selected from hydrogen, C 1-C 12Alkyl, C 2-C 12Thiazolinyl, C 2-C 12Hydroxyalkyl, C 2-C 12Hydroxy alkenyl, C 2-C 12Alkoxyalkyl, C 3-C 12Cyclic hydrocarbon radical, C 4-C 12Cyclic hydrocarbon radical alkyl, aryl, C 7-C 19Aralkyl, C 3-C 12Heterocyclic radical, C 3-C 12Heterocyclic radical alkyl, C 1-C 12Heteroaryl and C 3-C 12Heteroaryl alkyl;
Or R 3For having the multiring structure of 2 to 4 rings, wherein said ring is independently selected from cyclic hydrocarbon radical, heterocyclic radical, aryl and heteroaryl, and wherein part or all of described ring can condense each other;
Each R 4Be independently selected from hydrogen, fluorine, chlorine, C 1-C 12Alkyl, C 1-C 12Alkoxyl, haloalkyl, cyano group, nitro or-N (R 9) 2
Perhaps two adjacent R 4Group can form aryl, heteroaryl or heterocyclic ring system together with its carbon that is connected;
R 5, R 5a, R 6, R 6a, R 7, R 7a, R 8And R 8aAll be independently selected from hydrogen or C 1-C 3Alkyl;
Perhaps R 5With R 5aR together, 6With R 6aTogether or R 7With R 7aTogether or R 8With R 8aBe oxo group together;
Perhaps R 5, R 5a, R 6And R 6aOne of and R 7, R 7a, R 8And R 8aOne of form chemical bond or alkylidene bridge together, and remaining R 5, R 5a, R 6, R 6a, R 7, R 7a, R 8And R 8aAll be independently selected from hydrogen or C 1-C 3Alkyl;
Each R 9Be independently selected from hydrogen or C 1-C 6Alkyl; And
R 10Be independently selected from hydrogen, fluorine, chlorine, C 1-C 12Alkyl or C 1-C 12Alkoxyl.
2. treat mammiferous by the disease of stearoyl-CoA desaturase (SCD) mediation or the method for morbid state, wherein said method comprise will the treatment effective dose general formula (I) chemical compound to the described mammal administration of the described treatment of needs,
Figure A2005800397870003C1
Wherein:
X and y all are 0,1,2 or 3 independently;
G is-N (R 4)-,-O-,-S (O) t-(wherein t is 0,1 or 2) ,-C (R 4)=or-C (R 4)=C (R 4)-;
J and K all are N or C (R independently 10);
L and M each be independently-N=,-N (R 4)-or-C (R 4)=, but prerequisite are to be-C (R as G 4)=or-C (R 4)=C (R 4)-time, L and M are not-C (R simultaneously 4)=;
W be chemical bond ,-N (R 1) C (O)-,-C (O) N (R 1)-,-OC (O) N (R 1)-,-N (R 1) C (O) N (R 1)-,-O-,-N (R 1)-,-S (O) t-(wherein t is 0,1 or 2) ,-N (R 1) S (O) p-(wherein p is 1 or 2) ,-S (O) pN (R 1)-(wherein p be 1 or 2) ,-C (O)-,-OS (O) 2N (R 1)-,-OC (O)-,-C (O) O-or-N (R 1) C (O) O-;
Each R 1Be independently selected from hydrogen, C 1-C 12Alkyl, C 2-C 12Hydroxyalkyl, C 4-C 12Cyclic hydrocarbon radical alkyl and C 7-C 19Aralkyl;
R 2Be selected from C 1-C 12Alkyl, C 2-C 12Thiazolinyl, C 2-C 12Hydroxyalkyl, C 2-C 12Hydroxy alkenyl, C 2-C 12Alkoxyalkyl, C 3-C 12Cyclic hydrocarbon radical, C 4-C 12Cyclic hydrocarbon radical alkyl, aryl, C 7-C 19Aralkyl, C 3-C 12Heterocyclic radical, C 3-C 12Heterocyclic radical alkyl, C 1-C 12Heteroaryl and C 3-C 12Heteroaryl alkyl;
Or R 2For having the multiring structure of 2 to 4 rings, wherein said ring is independently selected from cyclic hydrocarbon radical, heterocyclic radical, aryl and heteroaryl, and wherein part or all of described ring can condense each other;
R 3Be selected from hydrogen, C 1-C 12Alkyl, C 2-C 12Thiazolinyl, C 2-C 12Hydroxyalkyl, C 2-C 12Hydroxy alkenyl, C 2-C 12Alkoxyalkyl, C 3-C 12Cyclic hydrocarbon radical, C 4-C 12Cyclic hydrocarbon radical alkyl, aryl, C 7-C 19Aralkyl, C 3-C 12Heterocyclic radical, C 3-C 12Heterocyclic radical alkyl, C 1-C 12Heteroaryl and C 3-C 12Heteroaryl alkyl;
Or R 3For having the multiring structure of 2 to 4 rings, wherein said ring is independently selected from cyclic hydrocarbon radical, heterocyclic radical, aryl and heteroaryl, and wherein part or all of described ring can condense each other;
Each R 4Be independently selected from hydrogen, fluorine, chlorine, C 1-C 12Alkyl, C 1-C 12Alkoxyl, haloalkyl, cyano group, nitro or-N (R 9) 2
Perhaps two adjacent R 4Group can form aryl, heteroaryl or heterocyclic ring system with the carbon that it connected;
R 5, R 5a, R 6, R 6a, R 7, R 7a, R 8And R 8aAll be independently selected from hydrogen or C 1-C 3Alkyl;
Perhaps R 5With R 5aR together, 6With R 6aTogether or R 7With R 7aTogether or R 8With R 8aBe oxo group together;
Perhaps R 5, R 5a, R 6And R 6aOne of and R 7, R 7a, R 8And R 8aOne of form chemical bond or alkylidene bridge together, and remaining R 5, R 5a, R 6, R 6a, R 7, R 7a, R 8And R 8aAll be independently selected from hydrogen or C 1-C 3Alkyl;
Each R 9Be independently selected from hydrogen or C 1-C 6Alkyl; And
R 10Be independently selected from hydrogen, fluorine, chlorine, C 1-C 12Alkyl or C 1-C 12Alkoxyl.
3. method as claimed in claim 2, wherein said mammal are human.
4. method as claimed in claim 3, wherein said disease or morbid state are selected from type ii diabetes, glucose tolerance attenuating, insulin resistant, obesity, fatty liver, non-alcoholic stellato-hepatitis, dyslipidemia and metabolism syndrome and above-mentioned combination in any.
5. method as claimed in claim 4, wherein said disease or morbid state are type ii diabetes.
6. method as claimed in claim 4, wherein said disease or morbid state are obesity.
7. method as claimed in claim 4, wherein said disease or morbid state are metabolism syndrome.
8. method as claimed in claim 4, wherein said disease or morbid state are fatty liver.
9. method as claimed in claim 4, wherein said disease or morbid state are non-alcoholic stellato-hepatitis.
10. general formula (I) chemical compound:
Figure A2005800397870005C1
Wherein:
X and y all are 0,1,2 or 3 independently;
G is-N (R 4)-,-O-,-S (O) t-(wherein t is 0,1 or 2) ,-C (R 4)=or-C (R 4)=C (R 4)-;
J and K all are N or C (R independently 10);
L and M all be independently-N=,-N (R 4)-or-C (R 4)=, but prerequisite are to be-C (R as G 4)=or-C (R 4)=C (R 4)-time, L and M are not-C (R simultaneously 4)=;
W be chemical bond ,-N (R 1) C (O)-,-C (O) N (R 1)-,-OC (O) N (R 1)-,-N (R 1) C (O) N (R 1)-,-O-,-N (R 1)-,-S (O) t-(wherein t is 0,1 or 2) ,-N (R 1) S (O) p-(wherein p is 1 or 2) ,-S (O) pN (R 1)-(wherein p be 1 or 2) ,-C (O)-,-OS (O) 2N (R 1)-,-OC (O)-,-C (O) O-or-N (R 1) C (O) O-;
Each R 1Be independently selected from hydrogen, C 1-C 12Alkyl, C 2-C 12Hydroxyalkyl, C 4-C 12Cyclic hydrocarbon radical alkyl and C 7-C 19Aralkyl;
R 2Be selected from C 1-C 12Alkyl, C 2-C 12Thiazolinyl, C 2-C 12Hydroxyalkyl, C 2-C 12Hydroxy alkenyl, C 2-C 12Alkoxyalkyl, C 3-C 12Cyclic hydrocarbon radical, C 4-C 12Cyclic hydrocarbon radical alkyl, aryl, C 7-C 19Aralkyl, C 3-C 12Heterocyclic radical, C 3-C 12Heterocyclic radical alkyl, C 1-C 12Heteroaryl and C 3-C 12Heteroaryl alkyl;
Or R 2For having the multiring structure of 2 to 4 rings, wherein said ring is independently selected from cyclic hydrocarbon radical, heterocyclic radical, aryl and heteroaryl, and wherein part or all of described ring can condense each other;
R 3Be selected from hydrogen, C 1-C 12Alkyl, C 2-C 12Thiazolinyl, C 2-C 12Hydroxyalkyl, C 2-C 12Hydroxy alkenyl, C 2-C 12Alkoxyalkyl, C 3-C 12Cyclic hydrocarbon radical, C 4-C 12Cyclic hydrocarbon radical alkyl, aryl, C 7-C 19Aralkyl, C 3-C 12Heterocyclic radical, C 3-C 12Heterocyclic radical alkyl, C 1-C 12Heteroaryl and C 3-C 12Heteroaryl alkyl;
Or R 3For having the multiring structure of 2 to 4 rings, wherein said ring is independently selected from cyclic hydrocarbon radical, heterocyclic radical, aryl and heteroaryl, and wherein part or all of described ring can condense each other;
Each R 4Be independently selected from hydrogen, fluorine, chlorine, C 1-C 12Alkyl, C 1-C 12Alkoxyl, haloalkyl, cyano group, nitro or-N (R 9) 2
Perhaps two adjacent R 4Group can form aryl, heteroaryl or heterocyclic ring system with the carbon that it connected;
R 5, R 5a, R 6, R 6a, R 7, R 7a, R 8And R 8aAll be independently selected from hydrogen or C 1-C 3Alkyl;
Perhaps R 5With R 5aR together, 6With R 6aTogether or R 7With R 7aTogether or R 8With R 8aBe oxo group together;
Perhaps R 5, R 5a, R 6And R 6aOne of and R 7, R 7a, R 8And R 8aOne of form chemical bond or alkylidene bridge together, and remaining R 5, R 5a, R 6, R 6a, R 7, R 7a, R 8And R 8aAll be independently selected from hydrogen or C 1-C 3Alkyl;
Each R 9Be independently selected from hydrogen or C 1-C 6Alkyl; And
R 10Be independently selected from hydrogen, fluorine, chlorine, C 1-C 12Alkyl or C 1-C 12Alkoxyl.
11. chemical compound as claimed in claim 10, wherein J and K are N, promptly have the chemical compound of following general formula (Ia):
Figure A2005800397870007C1
12. chemical compound as claimed in claim 11, wherein:
X and y are 1;
G is-C (R 4)=C (R 4)-;
L and M are-N=;
W is-N (R 1) C (O)-,-C (O) N (R 1)-,-OC (O) N (R 1)-,-N (R 1) C (O) N (R 1)-,-N (R 1) S (O) p-(wherein p is 1 or 2) ,-S (O) pN (R 1)-(wherein p be 1 or 2) ,-OS (O) 2N (R 1)-,-C (O) O-or-N (R 1) C (O) O-;
Each R 1Be independently selected from hydrogen, C 1-C 12Alkyl, C 2-C 12Hydroxyalkyl, C 4-C 12Cyclic hydrocarbon radical alkyl and C 7-C 19Aralkyl;
R 2Be selected from C 7-C 12Alkyl, C 2-C 12Thiazolinyl, C 7-C 12Hydroxyalkyl, C 2-C 12Hydroxy alkenyl, C 2-C 12Alkoxyalkyl, C 3-C 12Cyclic hydrocarbon radical, C 4-C 12Cyclic hydrocarbon radical alkyl, aryl, C 13-C 19Aralkyl, C 3-C 12Heterocyclic radical, C 3-C 12Heterocyclic radical alkyl, C 1-C 12Heteroaryl and C 3-C 12Heteroaryl alkyl;
R 3Be selected from aryl, C 3-C 12Heterocyclic radical and C 1-C 12Heteroaryl; And
Each R 4Be independently selected from hydrogen, fluorine, chlorine, C 1-C 12Alkyl, C 1-C 12Alkoxyl, haloalkyl, cyano group, nitro or-N (R 9) 2
R 5, R 5a, R 6, R 6a, R 7, R 7a, R 8And R 8aAll be independently selected from hydrogen or C 1-C 3Alkyl;
But prerequisite is R 2Be not C 5-C 10Pyrazinyl alkyl, pyriconyl, pyrrolidone-base, methylimidazolyl or the phenyl that is replaced by amino.
13. chemical compound as claimed in claim 12, wherein R 3Be aryl.
14. chemical compound as claimed in claim 13, it is selected from as follows:
6-[4-(4-fluorophenyl)-piperazine-1-yl]-pyridazine-3-carboxylic acid (2-cyclopropyl ethyl) amide; And
6-[4-(3-trifluoromethyl)-piperazine-1-yl]-pyridazine-3-carboxylic acid (2-cyclopropyl ethyl) amide.
15. chemical compound as claimed in claim 12, wherein R 3Be C 1-C 12Heteroaryl.
16. chemical compound as claimed in claim 15, it is selected from as follows:
6-(4-benzoxazole-2-base-piperazine-1-yl) pyridazine-3-carboxylic acid (2-cyclopropyl ethyl) amide;
6-(4-benzothiazole-2-base-piperazine-1-yl) pyridazine-3-carboxylic acid (2-cyclopropyl ethyl) amide;
6-(4-quinazoline-4-base-piperazine-1-yl) pyridazine-3-carboxylic acid (2-cyclopropyl ethyl) amide;
6-[4-(3-5-flumethiazine-2-yl) piperazine-1-yl] pyridazine-3-carboxylic acid (2-cyclopropyl ethyl) amide;
6-(4-benzo [d] isothiazole-3-base-piperazine-1-yl) pyridazine-3-carboxylic acid (2-cyclopropyl ethyl) amide;
6-(4-pyridine-2-base-piperazine-1-yl) pyridazine-3-carboxylic acid (2-cyclopropyl ethyl) amide; And
6-[4-(3-oxo-3H-iso-indoles-1-yl) piperazine-1-yl) pyridazine-3-carboxylic acid (2-cyclopropyl ethyl) amide.
17. pharmaceutical composition, it comprises general formula (I) chemical compound of pharmaceutically-acceptable excipients or carrier and treatment effective dose:
Figure A2005800397870008C1
Wherein:
X and y all are 0,1,2 or 3 independently;
G is-N (R 4)-,-O-,-S (O) t-(wherein t is 0,1 or 2) ,-C (R 4)=or-C (R 4)=C (R 4)-;
J and K all are N or C (R independently 10);
L and M all be independently-N=,-N (R 4)-or-C (R 4)=, but prerequisite are to be-C (R as G 4)=or-C (R 4)=C (R 4)-time, L and M are not-C (R simultaneously 4)=;
W be chemical bond ,-N (R 1) C (O)-,-C (O) N (R 1)-,-OC (O) N (R 1)-,-N (R 1) C (O) N (R 1)-,-O-,-N (R 1)-,-S (O) t-(wherein t is 0,1 or 2) ,-N (R 1) S (O) p-,-S (O) pN (R 1)-(wherein p be 1 or 2) ,-C (O)-,-OS (O) 2N (R 1)-,-OC (O)-,-C (O) O-or-N (R 1) C (O) O-;
Each R 1Be independently selected from hydrogen, C 1-C 12Alkyl, C 2-C 12Hydroxyalkyl, C 4-C 12Cyclic hydrocarbon radical alkyl and C 7-C 19Aralkyl;
R 2Be selected from C 1-C 12Alkyl, C 2-C 12Thiazolinyl, C 2-C 12Hydroxyalkyl, C 2-C 12Hydroxy alkenyl, C 2-C 12Alkoxyalkyl, C 3-C 12Cyclic hydrocarbon radical, C 4-C 12Cyclic hydrocarbon radical alkyl, aryl, C 7-C 19Aralkyl, C 3-C 12Heterocyclic radical, C 3-C 12Heterocyclic radical alkyl, C 1-C 12Heteroaryl and C 3-C 12Heteroaryl alkyl;
Or R 2For having the multiring structure of 2 to 4 rings, wherein said ring is independently selected from cyclic hydrocarbon radical, heterocyclic radical, aryl and heteroaryl, and wherein part or all of described ring can condense each other;
R 3Be selected from hydrogen, C 1-C 12Alkyl, C 2-C 12Thiazolinyl, C 2-C 12Hydroxyalkyl, C 2-C 12Hydroxy alkenyl, C 2-C 12Alkoxyalkyl, C 3-C 12Cyclic hydrocarbon radical, C 4-C 12Cyclic hydrocarbon radical alkyl, aryl, C 7-C 19Aralkyl, C 3-C 12Heterocyclic radical, C 3-C 12Heterocyclic radical alkyl, C 1-C 12Heteroaryl and C 3-C 12Heteroaryl alkyl;
Or R 3For having the multiring structure of 2 to 4 rings, wherein said ring is independently selected from cyclic hydrocarbon radical, heterocyclic radical, aryl and heteroaryl, and wherein part or all of described ring can condense each other;
Each R 4Be independently selected from hydrogen, fluorine, chlorine, C 1-C 12Alkyl, C 1-C 12Alkoxyl, haloalkyl, cyano group, nitro or-N (R 9) 2
Perhaps two adjacent R 4Group can form aryl, heteroaryl or heterocyclic ring system with the carbon that it connected;
R 5, R 5a, R 6, R 6a, R 7, R 7a, R 8And R 8aAll be independently selected from hydrogen or C 1-C 3Alkyl;
Perhaps R 5With R 5aR together, 6With R 6aTogether or R 7With R 7aTogether or R 8With R 8aBe oxo group together;
Perhaps R 5, R 5a, R 6And R 6aOne of and R 7, R 7a, R 8And R 8aOne of form chemical bond or alkylidene bridge together, and remaining R 5, R 5a, R 6, R 6a, R 7, R 7a, R 8And R 8aAll be independently selected from hydrogen or C 1-C 3Alkyl;
Each R 9Be independently selected from hydrogen or C 1-C 6Alkyl; And
R 10Be independently selected from hydrogen, fluorine, chlorine, C 1-C 12Alkyl or C 1-C 12Alkoxyl.
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